RESUMO
The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on the three-dimensional (3D) epigenome by mapping chromatin interactions and accessibility in control versus SATB2-deficient cortical neurons. We find that SATB2 affects the chromatin looping between enhancers and promoters of neuronal-activity-regulated genes, thus influencing their expression. It also alters A/B compartments, topologically associating domains, and frequently interacting regions. Genes linked to SATB2-dependent 3D genome changes are implicated in highly specialized neuronal functions and contribute to cognitive ability and risk for neuropsychiatric and neurodevelopmental disorders. Non-coding DNA regions with a SATB2-dependent structure are enriched for common variants associated with educational attainment, intelligence, and schizophrenia. Our data establish SATB2 as a cell-type-specific 3D genome modulator, which operates both independently and in cooperation with CCCTC-binding factor (CTCF) to set up the chromatin landscape of pyramidal neurons for cognitive processes.
Assuntos
Proteínas de Ligação à Região de Interação com a Matriz , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neurônios/metabolismo , Fator de Ligação a CCCTC/metabolismo , Cromatina/genética , Cromatina/metabolismo , Genoma , Cognição , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismoRESUMO
Long interspersed element-1 (LINE-1 or L1) comprises 17% of the human genome, continuously generates genetic variations, and causes disease in certain cases. However, the regulation and function of L1 remain poorly understood. Here, we uncover that L1 can enrich RNA polymerase IIs (RNA Pol IIs), express L1 chimeric transcripts, and create contact domain boundaries in human cells. This impact of L1 is restricted by a nuclear matrix protein scaffold attachment factor B (SAFB) that recognizes transcriptionally active L1s by binding L1 transcripts to inhibit RNA Pol II enrichment. Acute inhibition of RNA Pol II transcription abolishes the domain boundaries associated with L1 chimeric transcripts, indicating a transcription-dependent mechanism. Deleting L1 impairs domain boundary formation, and L1 insertions during evolution have introduced species-specific domain boundaries. Our data show that L1 can create RNA Pol II-enriched regions that alter genome organization and that SAFB regulates L1 and RNA Pol II activity to preserve gene regulation.
Assuntos
Elementos Nucleotídeos Longos e Dispersos , Proteínas de Ligação à Região de Interação com a Matriz , RNA Polimerase II , Receptores de Estrogênio , Transcrição Gênica , Humanos , RNA Polimerase II/metabolismo , RNA Polimerase II/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas Associadas à Matriz Nuclear/genética , Regulação da Expressão Gênica , Ligação Proteica , Células HEK293 , Genoma HumanoRESUMO
Despite the conservation of genetic machinery involved in eye development, there is a strong diversity in the placement of eyes on the head of animals. Morphogen gradients of signaling molecules are vital to patterning cues. During Drosophila eye development, Wingless (Wg), a ligand of Wnt/Wg signaling, is expressed anterolaterally to form a morphogen gradient to determine the eye- versus head-specific cell fate. The underlying mechanisms that regulate this process are yet to be fully understood. We characterized defective proventriculus (dve) (Drosophila ortholog of human SATB1), a K50 homeodomain transcription factor, as a dorsal eye gene, which regulates Wg signaling to determine eye versus head fate. Across Drosophila species, Dve is expressed in the dorsal head vertex region where it regulates wg transcription. Second, Dve suppresses eye fate by down-regulating retinal determination genes. Third, the dve-expressing dorsal head vertex region is important for Wg-mediated inhibition of retinal cell fate, as eliminating the Dve-expressing cells or preventing Wg transport from these dve-expressing cells leads to a dramatic expansion of the eye field. Together, these findings suggest that Dve regulates Wg expression in the dorsal head vertex, which is critical for determining eye versus head fate. Gain-of-function of SATB1 exhibits an eye fate suppression phenotype similar to Dve. Our data demonstrate a conserved role for Dve/SATB1 in the positioning of eyes on the head and the interocular distance by regulating Wg. This study provides evidence that dysregulation of the Wg morphogen gradient results in developmental defects such as hypertelorism in humans where disproportionate interocular distance and facial anomalies are reported.
Assuntos
Proteínas de Drosophila , Proteínas de Ligação à Região de Interação com a Matriz , Animais , Humanos , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , Drosophila/genética , Retina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Drosophila melanogaster/metabolismo , Padronização Corporal/genéticaRESUMO
Aging leads to an accumulation of cellular mutations and damage, increasing the risk of senescence, apoptosis, and malignant transformation. Cellular senescence, which is pivotal in aging, acts as both a guard against cellular transformation and as a check against cancer progression. It is marked by stable cell cycle arrest, widespread macromolecular changes, a pro-inflammatory profile, and altered gene expression. However, it remains to be determined whether these differing subsets of senescent cells result from unique intrinsic programs or are influenced by their environmental contexts. Multiple transcription regulators and chromatin modifiers contribute to these alterations. Special AT-rich sequence-binding protein 1 (SATB1) stands out as a crucial regulator in this process, orchestrating gene expression by structuring chromatin into loop domains and anchoring DNA elements. This review provides an overview of cellular senescence and delves into the role of SATB1 in senescence-related diseases. It highlights SATB1's potential in developing antiaging and anticancer strategies, potentially contributing to improved quality of life and addressing aging-related diseases.
Assuntos
Senescência Celular , Proteínas de Ligação à Região de Interação com a Matriz , Humanos , Senescência Celular/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Envelhecimento/genética , Envelhecimento/patologia , Envelhecimento/metabolismo , Animais , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Cromatina/metabolismo , Cromatina/genéticaRESUMO
BACKGROUND: It is known that the neurodevelopmental disorder associated gene, Satb2, plays important roles in determining the upper layer neuron specification. However, it is not well known how this gene regulates other neocortical regions during the development. It is also lack of comprehensive delineation of its spatially regulatory pathways in neocortical development. RESULTS: In this work, we utilized spatial transcriptomics and immuno-staining to systematically investigate the region-specific gene regulation of Satb2 by comparing the Satb2+/+ and Satb2-/- mice at embryonic stages, including the ventricle zone (VZ) or subventricle zone (SVZ), intermediate zone (IZ) and cortical plate (CP) respectively. The staining result reveals that these three regions become moderately or significantly thinner in the Satb2-/- mice. In the cellular level, the cell number increases in the VZ/SVZ, whereas the cell number decreases in the CP. The spatial transcriptomics data show that many important genes and relevant pathways are dysregulated in Satb2-/- mice in a region-specific manner. In the VZ/SVZ, the key genes involved in neural precursor cell proliferation, including the intermediate progenitor marker Tbr2 and the lactate production related gene Ldha, are up-regulated in Satb2-/- mice. In the IZ, the key genes in regulating neuronal differentiation and migration, such as Rnd2, exhibit ectopic expressions in the Satb2-/- mice. In the CP, the lineage-specific genes, Tbr1 and Bcl11b, are abnormally expressed. The neuropeptide related gene Npy is down-regulated in Satb2-/- mice. Finally, we validated the abnormal expressions of key regulators by using immunofluorescence or qPCR. CONCLUSIONS: In summary, our work provides insights on the region-specific genes and pathways which are regulated by Satb2 in neocortical development.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Ligação à Região de Interação com a Matriz , Neocórtex , Fatores de Transcrição , Transcriptoma , Animais , Neocórtex/metabolismo , Neocórtex/crescimento & desenvolvimento , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Camundongos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Perfilação da Expressão Gênica , Camundongos Knockout , Proteínas Repressoras , Proteínas Supressoras de TumorRESUMO
Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) originates from the T-lineage and is marked by rearrangements of the ALK gene. More than 10 fusion partners with the ALK gene are known, with the most common being the t(2;5)(p23;q35) translocation resulting in the NPM1::ALK fusion. In 10% to 20% of the ALK+ ALCL cases, the ALK gene fuses with various other partners. Modern molecular techniques, especially next-generation sequencing (NGS), have eased the identification of ALK gene fusion partners and have allowed in-depth characterization of the T-cell receptor (TCR) repertoire. We devised a real-time quantitative reverse-transcription polymerase chain reaction to measure the expression of the translocated portion of the ALK gene. Fusion partners for the ALK gene were analyzed using rapid amplification of 5'cDNA ends (RACE) method or NGS. TCR immunoprofiling was performed by amplicon NGS. We studied 96 ALK+ ALCL patients. NPM1::ALK fusion gene was observed in 71 patients, ATIC::ALK in 9, and TPM3::ALK in 3. CLTC::ALK, MYH9::ALK, and RNF213::ALK fusions were identified in 2 patients each. We also discovered the TPM4::ALK and SATB1::ALK fusion genes, plus the following 2 previously unidentified ALK+ ALCL fusions: SQSTM1::ALK and CAPRIN1::ALK. High expression of the translocated ALK gene segment was observed in all 93 analyzed samples. TCR testing was conducted on 23 patients with available DNA. In 18 (78%) patients, we discerned at least one (ranging from 1 to 4) clonal TCR rearrangement. In 59% of the patients, clonal TCR beta junctions corresponded with sequences previously observed in both healthy donors and under various pathological conditions. Reverse-transcriptase quantitative detection of ALK expression is a fast and reliable method for both diagnosing and monitoring treatment response in ALK+ ALCL patients, irrespective of the ALK gene translocation. NGS reveals new ALK translocation partners. Both malignant and reactive TCR repertoires in ALK+ ALCL patients are unique and do not consistently occur among different patients.
Assuntos
Linfoma Anaplásico de Células Grandes , Proteínas de Ligação à Região de Interação com a Matriz , Ubiquitina-Proteína Ligases , Humanos , Quinase do Linfoma Anaplásico/genética , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Receptores Proteína Tirosina Quinases/genética , Proteínas Tirosina Quinases/genética , Translocação Genética , Fatores de Transcrição/genética , Proteínas Nucleares/genética , Receptores de Antígenos de Linfócitos T/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Ciclo Celular/genética , Adenosina Trifosfatases/genéticaRESUMO
SATB2-associated syndrome (SAS, glass syndrome, OMIM#612313) is a neurodevelopmental autosomal dominant disorder with frequent craniofacial abnormalities including palatal and dental anomalies. To assess the role of Satb2 in craniofacial development, we analyzed mutant mice at different stages of development. Here, we show that Satb2 is broadly expressed in early embryonic mouse development including the mesenchyme of the second and third arches. Satb2-/- mutant mice exhibit microglossia, a shortened lower jaw, smaller trigeminal ganglia, and larger thyroids. We correlate these findings with the detailed clinical phenotype of four individuals with SAS and remarkable craniofacial phenotypes with one requiring mandibular distraction in childhood. We conclude that the mouse and patient data presented support less well-described phenotypic aspects of SAS including mandibular morphology and thyroid anatomical/functional issues.
Assuntos
Região Branquial , Proteínas de Ligação à Região de Interação com a Matriz , Fenótipo , Fatores de Transcrição , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Animais , Humanos , Camundongos , Fatores de Transcrição/genética , Região Branquial/anormalidades , Região Branquial/patologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Feminino , Masculino , Camundongos Knockout , Síndrome , Mandíbula/anormalidades , Mandíbula/patologiaRESUMO
Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy of the head and neck epidermis. Accumulating long non-coding RNAs (lncRNAs) have been proven to be involved in the occurrence and development of HNSCC. LncRNA long intergenic non-protein coding RNA 491 (LINC00491) has been confirmed to regulate the progression of some cancers. In our study, we aimed to explore the potential biological function of LINC00491 and expound the regulatory mechanism by which LINC00491 affects the progression of HNSCC. RT-qPCR was utilized to analyze the expression of LINC00491 in HNSCC cell lines and the normal cell line. Functionally, we carried out a series of assays to measure cell proliferation, apoptosis, migration and invasion, such as EdU assay, colony formation, wound healing and western blot assays. Also, mechanism assays including RNA pull down and RIP were also implemented to investigate the interaction of LINC00491 and RNAs. As a result, we discovered that LINC00491 was highly expressed in HNSCC cells. In addition, LINC00491 depletion suppressed cell proliferation, migration and EMT process. Furthermore, we discovered that LINC00491 could bind to miR-508-3p. MiR-508-3p overexpression can restrain HNSCC cell growth. Importantly, miR-508-3p can target SATB homeobox 1 (SATB1) in HNSCC cells. Further, Wnt signaling pathway was proved to be activated by LINC00491 through SATB1 in HNSCC cells. In a word, LINC00491 accelerated HNSCC progression through regulating miR-508-3p/SATB1 axis and activating Wnt signaling pathway.
Assuntos
Neoplasias de Cabeça e Pescoço , Proteínas de Ligação à Região de Interação com a Matriz , MicroRNAs , RNA Longo não Codificante , Humanos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/genéticaRESUMO
CDX2 and SATB2 are often used as biomarkers for identification of colorectal origin in primary or metastatic adenocarcinomas. Loss of CDX2 or SATB2 expression has been associated with poor prognosis in patients with colorectal cancer (CRC). However, little is known regarding clinicopathological features, including prognosis, of CRCs with concomitant loss of CDX2 and SATB2. A total of 431 stage III CRCs were analyzed for their expression status in CDX2 and SATB2 using tissue microarray-based immunohistochemistry and expression status was correlated with clinicopathological variables, molecular alterations, and survival. CDX2-negative (CDX2-) CRCs and SATB2-negative (SATB2-) CRCs were found in 8.1 % and 17.2 % of CRCs, respectively, whereas both CDX2-negative and SATB2-negative (CDX2-/SATB2-) CRCs comprised 3.2 % of the CRCs. On survival analysis, neither CDX2-/SATB2+ nor CDX2+/SABT2- CRCs but CDX2-/SATB2- CRCs were associated with poor prognosis. CDX2-/SATB2- CRCs showed significant associations with tumor subsite of right colon, poor differentiation, decreased expression of CK20, aberrant expression of CK7, CIMP-high, MSI-high, and BRAF mutation. In summary, our results suggest that concomitant loss of CDX2 and SATB2 is a prognostic biomarker but isolated loss of CDX2 or SATB2 is not a prognostic biomarker for stage III CRCs.
Assuntos
Biomarcadores Tumorais , Fator de Transcrição CDX2 , Neoplasias Colorretais , Proteínas de Ligação à Região de Interação com a Matriz , Estadiamento de Neoplasias , Fatores de Transcrição , Humanos , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Fator de Transcrição CDX2/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Masculino , Fatores de Transcrição/metabolismo , Feminino , Biomarcadores Tumorais/metabolismo , Prognóstico , Idoso , Pessoa de Meia-Idade , Imuno-Histoquímica/métodos , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/diagnóstico , Adulto , Análise Serial de Tecidos , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Reliably distinguishing primary ovarian mucinous neoplasms (POMNs) from metastatic colorectal cancers (CRCs) is both challenging to the histopathologist and of great clinical importance. Special AT-rich sequence binding protein-2 (SATB2) has emerged as a useful diagnostic immunohistochemical marker of colorectal cancer. This meta-analysis compares SATB2 expression in POMNs and CRC. METHODS: A systematic literature search for relevant studies was conducted. Meta-analysis of SATB2 positivity was undertaken using a random effects model. RESULTS: Seven studies including 711 CRCs and 528 POMNs were included. SATB2 positivity was seen in 81 % (95 % CI: 72-88 %) of CRCs and 4 % (95 % CI: 1-11 %) of POMNs. Variation was seen in immunohistochemical methods used for SATB2 detection and threshold for positivity. CONCLUSION: SATB2 staining remains high in CRC and low in POMNs, supporting its use in differentiating these two pathologies with vastly differing prognosis and treatment.
Assuntos
Adenocarcinoma Mucinoso , Biomarcadores Tumorais , Neoplasias Colorretais , Imuno-Histoquímica , Proteínas de Ligação à Região de Interação com a Matriz , Neoplasias Ovarianas , Fatores de Transcrição , Humanos , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/diagnóstico , Feminino , Imuno-Histoquímica/métodos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Fatores de Transcrição/metabolismo , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/diagnóstico , Diagnóstico DiferencialRESUMO
Objective: To investigate the clinical and pathological characteristics of primary mucinous gland lesions of the fallopian tubes. Methods: The clinical data, pathomorphological characteristics and immunophenotype of 14 cases of primary mucinous gland lesions of the fallopian tube diagnosed at Obstetrics and Gynecology Hospital of Fudan University from 2015 to 2023 were analyzed retrospectively. In addition, a comprehensive review of relevant literature was conducted. Results: The age of 14 patients ranged from 53 to 83 years, with an average of 65 years. Among them, 13 cases exhibited unilateral involvement while one case showed bilateral presentation. Nine cases were mucinous metaplasia of the fallopian tube, four cases were invasive mucinous adenocarcinoma and one case was mucinous carcinoma in situ. Morphologically, mucinous metaplasia of the fallopian tube was focal, with or without inflammation. The cells of mucinous adenocarcinoma or mucinous carcinoma in situ exhibited characteristics indicative of gastrointestinal differentiation. Immunohistochemical analysis revealed diffuse positive expression of CK7, and negative expression of SATB2. CDX2 demonstrated positive staining in two cases. One case exhibited diffuse and strongly positive mutant expression of p53, whereas the remaining cases displayed wild-type expression. MUC6 showed diffuse or focally positive staining in mucinous gland lesions characterized by gastric differentiation. Some cases of mucinous adenocarcinoma of fallopian tube were subject to AB-PAS staining, resulting in red to purple cytoplasmic staining. Conclusions: Primary mucinous lesions of the fallopian tube are exceedingly uncommon. All cases of mucinous adenocarcinoma of fallopian tubes in this study exhibit the morphology and immunohistochemical characteristics of gastrointestinal differentiation. Mucinous metaplasia of the fallopian tube is a benign lesion of incidental finding, which is closely related to inflammation or gastric differentiation. Mucinous lesions of cervix, ovary and digestive tract are excluded in all patients, confirming the independent existence of mucinous lesions within fallopian tubes.
Assuntos
Adenocarcinoma Mucinoso , Neoplasias das Tubas Uterinas , Tubas Uterinas , Metaplasia , Proteína Supressora de Tumor p53 , Humanos , Feminino , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/metabolismo , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/metabolismo , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Tubas Uterinas/patologia , Idoso de 80 Anos ou mais , Proteína Supressora de Tumor p53/metabolismo , Metaplasia/patologia , Queratina-7/metabolismo , Fator de Transcrição CDX2/metabolismo , Fator de Transcrição CDX2/genética , Mucina-6/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Carcinoma in Situ/patologia , Imuno-HistoquímicaRESUMO
This study aimed to investigate the possible mechanism of Micro RNA-548b-5p (miR-548b-5p) down-regulating frizzled (FZD) 7 to suppress the migration and invasion of gastric carcinoma cells. For this purpose, HGCC (Human gastric carcinoma cell) lines were selected (Hs-746T, NCI-N87, SGC-7901, MKN-45, SNU-1), and human normal gastric mucosa cells GES-1. QRT PCR was adopted to reveal and screen the cell line with low expression of mir-548b-5p (hs-746t) for research; the Hs-746T cells were randomly assigned into control group, miR-548b-5p NC group, miR-548b-5p mimic group, miR-548b-5p mimic+pc-FZD7 group. The CCK-8 assay was utilized to measure Hs-746T cell viability, while flow cytometry, Trans well chamber, and scratch test were utilized to examine the apoptotic, invasive, and migratory properties of the cells, respectively. WB was used to detect the SATB1, as well as the expression levels of proteins involved in apoptosis, including Caspase-3, Bax, and Bcl-2, as well as Matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9) in SW620 cells. The binding of miR-548b-5p to FZD7 was evaluated through the dual-luciferase reporter assay. The results indicate that MiR-548b-5p showed low expression in HGCCs; in contrast to the control group (P>0.05), the Hs-746T cell viability, invasion, migration ability, MMP-2, MMP-9 protein significantly downregulated in miR-548b-5p mimic group (P<0.05), the apoptosis rate, Caspase-3, Bax protein expression were upregulated markedly, and Bcl-2 protein expression was downregulated significantly (P<0.05); in contrast to miR-548b-5p mimic group, the Hs-746T cell viability, invasion, migration ability, MMP-2, MMP-9 protein significantly were upregulated in miR-548b-5p mimic+pc-FZD7 group (P<0.05), the apoptosis rate, Caspase-3, Bax protein expression were significantly, and the level of Bcl-2 was down-regulated significantly (P<0.05); Double Luciferase Report shows that mir-548b-5p can target and regulate fzd7. It was concluded that MiR-548b-5p can suppress cell growth and migration of HGCC Hs-746T, which may be achieved by targeted down-regulation of FZD7.
Assuntos
Carcinoma , Receptores Frizzled , Proteínas de Ligação à Região de Interação com a Matriz , MicroRNAs , Humanos , Apoptose/genética , Proteína X Associada a bcl-2/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Luciferases/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoAssuntos
Fibroma Ossificante , Rearranjo Gênico , Proteínas de Ligação à Região de Interação com a Matriz , Fatores de Transcrição , Humanos , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Fibroma Ossificante/genética , Fibroma Ossificante/patologia , Fatores de Transcrição/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Masculino , Feminino , CriançaAssuntos
Colonoscopia , Neoplasias Colorretais , Humanos , Feminino , Neoplasias Colorretais/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Pessoa de Meia-Idade , Idoso , Adulto , Biópsia , Adenocarcinoma/secundário , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Neoplasias dos Genitais Femininos/patologia , Neoplasias dos Genitais Femininos/diagnóstico , Neoplasias dos Genitais Femininos/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/diagnóstico , Queratina-7/metabolismo , Cistadenocarcinoma Seroso/secundário , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/metabolismo , Proteínas WT1/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Diagnóstico Diferencial , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fatores de TranscriçãoRESUMO
Colorectal cancer (CRC) is a malignancy with high incidence and poor prognosis. It is urgent to identify valuable biomarkers for early diagnosis and potent therapeutic targets. It has been reported that SATB1 is associated with the malignant progression in CRC. To explore the role of SATB1 in CRC progression and the underlying mechanism, we evaluated the expression of SATB1 in the paired CRC tissues with immunohistochemistry. The results showed that the expression of SATB1 in lymph node metastasis was higher than that in primary lesion, and that in distant organ metastasis was higher than that in primary lesion. The retrospective analysis showed that patients with high expression of SATB1 had a significantly worse prognosis than those with negative and moderate expression. In vitro experiments that employing SATB1 over-expressing and depleted CRC cell lines confirmed that SATB1 contributes to cell proliferation and colonization, while inhibiting cell motility. Furthermore, the tissue immunofluorescence assay, Co-IP and Western blot were conducted to reveal that SATB1 induced translocation of ß-catenin and formed a protein complex with it in the nuclei. In conclusion, SATB1 mediated tumor colonization and ß-catenin nuclear localization are associated with the malignant progression and poor prognosis of CRC.
Assuntos
Neoplasias Colorretais , Proteínas de Ligação à Região de Interação com a Matriz , Humanos , beta Catenina/metabolismo , Neoplasias Colorretais/patologia , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Estudos Retrospectivos , Prognóstico , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proliferação de Células , Via de Sinalização WntRESUMO
Mutations in the SRCAP gene are among the genetic alterations identified in autism spectrum disorders (ASD). However, the pathogenic mechanisms remain unclear. In this study, we demonstrate that Srcap+/- mice manifest deficits in social novelty response, as well as increased repetitive behaviors, anxiety, and impairments in learning and memory. Notably, a reduction in parvalbumin-positive neurons is observed in the retrosplenial cortex (RSC) and dentate gyrus (DG) of these mice. Through RNA sequencing, we identify dysregulation in 27 ASD-related genes in Srcap+/- mice. Specifically, we find that Srcap regulates expression of Satb2 via H2A.z in the promoter. Therapeutic intervention via retro-orbital injection of adeno-associated virus (AAV)-Satb2 in neonatal Srcap+/- mice leads to amelioration of the neurodevelopmental and ASD-like abnormalities. Furthermore, the expression of Satb2 only in the RSC of adolescent mice rectifies social novelty impairments. These results underscore the pivotal role of Srcap in neurodevelopment, by regulating Satb2, providing valuable insights for the pathophysiology of ASD.
Assuntos
Haploinsuficiência , Proteínas de Ligação à Região de Interação com a Matriz , Fatores de Transcrição , Animais , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Camundongos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Comportamento Animal , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Masculino , Comportamento Social , Camundongos Endogâmicos C57BL , Neurônios/metabolismoRESUMO
Bladder cancer (BLCA) is a malignant tumor associated with unfavorable outcomes. Studies suggest that anoikis plays a crucial role in tumor progression and cancer cell metastasis. However, its specific role in bladder cancer remains poorly understood. Our objective was to identify anoikis-related genes (ARGs) and subsequently construct a risk model to assess their potential for predicting the prognosis of bladder cancer.The transcriptome data and clinical data of BLCA patients were sourced from The Cancer Genome Atlas and GEO database. We then performed the differential expression analysis to screen differentially expressed ARGs. Subsequently, we conducted non-negative matrix factorization (NMF) clustering analysis to establish molecular subtypes based on the differentially expressed ARGs. The CIBERSORT algorithm was used to estimate the quantification of different cell infiltration in BLCA tumor microenviroment. A prognostic risk model containing 7 ARGs was established using Lasso-Cox regression analysis. The nomogram was built for predicting the survival probability of BLCA patients. To determine the drug sensitivity of each sample from the high- and low-risk groups, the R package "pRRophetic" was performed. Finally, the role of LYPD1 was explored in BLCA cell lines.We identified 90 differential expression ARGs and NMF clustering categorizated the BLCA patientss into two distinct groups (cluster A and B). Patients in cluster A had a better prognosis than those in cluster B. Then, we established a ARGs risk model including CALR, FASN, FOSL1, JUN, LYPD1, MST1R, and SATB1, which was validated in the train and test set. The results suggested overall survival rate was much higher in low risk group than high risk group. The cox regression analysis, ROC curve analysis, and nomogram collectively demonstrated that the risk model served as an independent prognostic factor. The high risk group had a higher level TME scores compared to the low risk group. Furthermore, LYPD1 was low expression in BLCA cells and overexpression of LYPD1 inhibits the prolifearation, migration and invasion.In the current study, we have identified differential expression ARGs and constructed a risk model with the promise for guiding prognostic predictions and provided a therapeutic target for patients with BLCA.
Assuntos
Proteínas de Ligação à Região de Interação com a Matriz , Neoplasias da Bexiga Urinária , Humanos , Anoikis/genética , Neoplasias da Bexiga Urinária/genética , Genes Homeobox , Bexiga Urinária , Nomogramas , PrognósticoRESUMO
Recently identified human FOXP3lowCD45RA- inflammatory non-suppressive (INS) cells produce proinflammatory cytokines, exhibit reduced suppressiveness, and promote antitumor immunity unlike conventional regulatory T cells (Tregs). In spite of their implication in tumors, the mechanism for generation of FOXP3lowCD45RA- INS cells in vivo is unclear. We showed that the FOXP3lowCD45RA- cells in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in Tregs bore Foxp3lowINS-Tregs with mitochondrial dysfunction and metabolic reprograming. The enhanced glutaminolysis activated α-ketoglutarate-mTORC1 axis, which promoted proinflammatory cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased α-ketoglutarate-derived 2-hydroxyglutarate down-regulated Foxp3 expression by methylating the Foxp3 gene regulatory regions. Furthermore, CRIF1 deficiency-induced Foxp3lowINS-Tregs suppressed tumor growth in an IFN-γ-dependent manner. Thus, CRIF1 deficiency-mediated mitochondrial dysfunction results in the induction of Foxp3lowINS-Tregs including FOXP3lowCD45RA- cells that promote antitumor immunity.
Assuntos
Proteínas de Ligação à Região de Interação com a Matriz , Doenças Mitocondriais , Neoplasias , Humanos , Camundongos , Animais , Linfócitos T Reguladores , Ácidos Cetoglutáricos/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Citocinas/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismoRESUMO
Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in ARID1B+/- neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an in vitro model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2+ neurons as a cause of ACC in ARID1B patients.
Assuntos
Axônios , Corpo Caloso , Proteínas de Ligação a DNA , Organoides , Fatores de Transcrição , Humanos , Corpo Caloso/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Organoides/metabolismo , Axônios/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Transcrição Gênica , Neurônios/metabolismoRESUMO
BACKGROUND/AIM: Pancreatic cancer is one of the most lethal malignant cancers worldwide and the seventh most common cause of cancer-related death in both sexes. Herein, we analyzed open access data and discovered that expression of a gene called deoxynucleotidyltransferase terminal-interacting protein 2 (DNTTIP2) is linked to prognosis of pancreatic ductal adenocarcinoma (PDAC). We then elucidated the role of DNTTIP2 in the proliferation of pancreatic cancer cells in vitro. MATERIALS AND METHODS: A WST-8 assay, cell cycle analysis, Annexin-V staining, quantitative reverse transcription-PCR, and western blot analysis were conducted to assess cell proliferation, cell cycle, apoptosis, and expression of DNTTIP2 mRNA and protein, respectively, in DNTTIP2-depleteted MIA-PaCa-2 and PK-1 cells. RESULTS: Depletion of DNTTIP2 induced G1 arrest in MIA-PaCa-2 cells by decreasing expression of special AT-rich sequence binding protein 1 (SATB1) and cyclin-dependent kinase 6 (CDK6). In addition, depletion of DNTTIP2 induced G2 arrest in PK-1 cells by decreasing expression of CDK1. Depletion of DNTTIP2 did not induce apoptosis in MIA-PaCa-2 or PK-1 cells. CONCLUSION: DNTTIP2 is involved in proliferation of pancreatic cancer cells. Thus, DNTTIP2 is a potential target for inhibiting progression of pancreatic cancers.