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1.
Artigo em Inglês | MEDLINE | ID: mdl-33525735

RESUMO

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory genetic disorder characterized by recurrent fever attacks and systemic inflammation with potentially severe complications. Although it is recognized that the lack of protein prenylation consequent to mevalonate pathway blockade drives IL1ß hypersecretion, and hence autoinflammation, MKD pathogenesis and the molecular mechanisms underlaying most of its clinical manifestations are still largely unknown. In this study, we performed a comprehensive bioinformatic analysis of a microarray dataset of MKD patients, using gene ontology and Ingenuity Pathway Analysis (IPA) tools, in order to identify the most significant differentially expressed genes and infer their predicted relationships into biological processes, pathways, and networks. We found that hematopoiesis linked biological functions and pathways are predominant in the gene ontology of differentially expressed genes in MKD, in line with the observed clinical feature of anemia. We also provided novel information about the molecular mechanisms at the basis of the hematological abnormalities observed, that are linked to the chronic inflammation and to defective prenylation. Considering the broad and unspecific spectrum of MKD clinical manifestations and the difficulty in its diagnosis, a better understanding of MKD molecular bases could be translated to the clinical level to facilitate diagnosis, and improve management and therapy.


Assuntos
Deficiência de Mevalonato Quinase , Criança , Expressão Gênica , Hematopoese/genética , Humanos , Inflamação , Deficiência de Mevalonato Quinase/genética , Prenilação de Proteína
2.
Nat Commun ; 12(1): 821, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547282

RESUMO

Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10-8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Síndrome de Down/genética , Epigênese Genética , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Proteína Proto-Oncogênica c-fli-1/genética , Estudos de Casos e Controles , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Ilhas de CpG , Metilação de DNA , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Feminino , Feto , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Genoma Humano , Estudo de Associação Genômica Ampla , Células-Tronco Hematopoéticas/patologia , Humanos , Recém-Nascido , Fígado/metabolismo , Fígado/patologia , Masculino , Regiões Promotoras Genéticas , Proteína Proto-Oncogênica c-fli-1/metabolismo
3.
Mol Biol (Mosk) ; 55(1): 126-138, 2021.
Artigo em Russo | MEDLINE | ID: mdl-33566032

RESUMO

A study was made of the effect that mitomycin C (MitC) treatment of stromal layers of NIH 3T3 cells expressing Jagged1, a ligand of the Notch receptor, exerts on the growth of hematopoietic Lin(-) mouse bone marrow cells in a co-culture system. MitC treatment of stromal cells significantly increased the number of hematopoietic cells and the frequency of colony-forming cells in stromal co-cultures. Transcriptome analysis of control and MitC-treated stromal cell samples was performed by differential RNA sequencing, and genes downregulated by MitC treatment were predominantly associated with the control of cell proliferation, the cell cycle, chromosome segregation, and DNA metabolism. Induction of key hematopoietic cytokines by MitC was not detected by the transcriptome analysis and was therefore not a main factor in the activation of hematopoiesis on the treated stroma. At the same time, the set of the genes most strongly upregulated by MitC treatment is enriched in the genes for cytokines, growth factors, and cell surface proteins, which presumably contribute to enhanced hematopoiesis support on the MitC-treated stroma. Products of some of these genes have been implicated in expansion of hematopoietic stem/progenitor cells in vitro or in vivo.


Assuntos
Hematopoese , Mitomicina , Animais , Células da Medula Óssea , Células Cultivadas , Técnicas de Cocultura , Hematopoese/genética , Células-Tronco Hematopoéticas , Camundongos , Células Estromais
4.
Methods Mol Biol ; 2224: 153-182, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33606214

RESUMO

Hematopoiesis in the mouse and other mammals occurs in several waves and arises from distinct anatomic sites. Transgenic mice expressing fluorescent reporter proteins at various points in the hematopoietic hierarchy, from hematopoietic stem cell to more restricted progenitors to each of the final differentiated cell types, have provided valuable tools for tagging, tracking, and isolating these cells. In this chapter, we discuss general considerations in designing a transgene, survey available fluorescent probes, and describe methods for confirming and analyzing transgene expression in the hematopoietic tissues of the embryo, fetus, and postnatal/adult animal.


Assuntos
Genes Reporter/genética , Hematopoese/genética , Proteínas Luminescentes/genética , Animais , Diferenciação Celular/genética , Embrião de Mamíferos/fisiologia , Feminino , Feto/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Células-Tronco/fisiologia , Transgenes/genética
5.
Arterioscler Thromb Vasc Biol ; 41(3): 1012-1018, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33441024

RESUMO

The blood system is often represented as a tree-like structure with stem cells that give rise to mature blood cell types through a series of demarcated steps. Although this representation has served as a model of hierarchical tissue organization for decades, single-cell technologies are shedding new light on the abundance of cell type intermediates and the molecular mechanisms that ensure balanced replenishment of differentiated cells. In this Brief Review, we exemplify new insights into blood cell differentiation generated by single-cell RNA sequencing, summarize considerations for the application of this technology, and highlight innovations that are leading the way to understand hematopoiesis at the resolution of single cells. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Hematopoese/genética , RNA-Seq/métodos , Análise de Célula Única/métodos , Animais , Biologia Computacional/métodos , Biologia Computacional/tendências , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , RNA-Seq/estatística & dados numéricos , RNA-Seq/tendências , Análise de Célula Única/estatística & dados numéricos , Análise de Célula Única/tendências
6.
Nat Commun ; 12(1): 43, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397967

RESUMO

CCCTC binding factor (CTCF) is an important factor in the maintenance of chromatin-chromatin interactions, yet the mechanism regulating its binding to chromatin is unknown. We demonstrate that zinc finger protein 143 (ZNF143) is a key regulator for CTCF-bound promoter-enhancer loops. In the murine genome, a large percentage of CTCF and ZNF143 DNA binding motifs are distributed 37 bp apart in the convergent orientation. Furthermore, deletion of ZNF143 leads to loss of CTCF binding on promoter and enhancer regions associated with gene expression changes. CTCF-bound promoter-enhancer loops are also disrupted after excision of ZNF143. ZNF143-CTCF-bound promoter-enhancer loops regulate gene expression patterns essential for maintenance of murine hematopoietic stem and progenitor cell integrity. Our data suggest a common feature of gene regulation is that ZNF143 is a critical factor for CTCF-bound promoter-enhancer loops.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Elementos Facilitadores Genéticos , Células-Tronco Hematopoéticas/metabolismo , Regiões Promotoras Genéticas , Transativadores/metabolismo , Animais , DNA/metabolismo , Hematopoese/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Ligação Proteica , Estabilidade Proteica , Transcrição Genética
7.
Gene ; 764: 145101, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32877747

RESUMO

India is the world's largest milk producing country because of massive contribution made by cattle and buffaloes. In the present investigation, comprehensive comparative profiling of transcriptomic landscape of milk somatic cells of Sahiwal cattle and Murrah buffaloes was carried out. Genes with highest transcript abundance in both species were enriched for biological processes such as lactation, immune response, cellular oxidant detoxification and response to hormones. Analysis of differential expression identified 377 significantly up-regulated and 847 significantly down-regulated genes with fold change >1.5 in Murrah buffaloes as compared to Sahiwal cattle (padj <0.05). Marked enrichment of innate and adaptive immune response related GO terms and higher expression of genes for various host defense peptides such as lysozyme, defensin ß and granzymes were evident in buffaloes. Genes related to ECM-receptor interaction, complement and coagulation cascades, cytokine-cytokine receptor interaction and keratinization pathway showed more abundant expression in cattle. Network analysis of the up-regulated genes delineated highly connected genes representing immunity and haematopoietic cell lineage (CBL, CD28, CD247, PECAM1 and ITGA4). For the down-regulated dataset, genes with highest interactions were KRT18, FGFR1, GPR183, ITGB3 and DKK3. Our results lend support to more robust immune mechanisms in buffaloes, possibly explaining lower susceptibility to mammary infections as compared to cattle.


Assuntos
Búfalos/imunologia , Bovinos/imunologia , Imunidade/genética , Transcriptoma/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Búfalos/genética , Bovinos/genética , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Regulação para Baixo/imunologia , Feminino , Hematopoese/genética , Hematopoese/imunologia , Índia , Lactação/genética , Lactação/imunologia , Leite/citologia , Leite/imunologia , RNA-Seq , Transcriptoma/genética , Regulação para Cima/imunologia
8.
Yi Chuan ; 42(8): 725-738, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32952109

RESUMO

Hematopoiesis is a complex, orderly and conserved developmental process, coordinated by multiple factors including transcription factors and signaling pathways. Dysregulation of any of these factors may cause developmental or functional defects in the blood system, leading to the pathogenesis of blood diseases. Zebrafish hematopoiesis and the underlying molecular mechanisms are highly conserved with those in mammals. The use of zebrafish to recapitulate abnormal changes in pathogenic factors can build models of related blood diseases, thus providing powerful tools for exploring the molecular mechanisms of pathogenesis and progression, visualization of tumorigenesis and high-throughput chemical screening. In this review, we summarize the zebrafish models of blood diseases and their applications. These disease models not only help to improve our understanding of the pathophysiology of the blood system and the molecular mechanisms on pathogeneses of blood diseases, but also provide new ideas for the treatment of clinically relevant hematological malignancies.


Assuntos
Doenças Hematológicas , Peixe-Zebra , Animais , Modelos Animais de Doenças , Doenças Hematológicas/genética , Neoplasias Hematológicas/fisiopatologia , Hematopoese/genética
9.
Proc Natl Acad Sci U S A ; 117(41): 25655-25666, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32978299

RESUMO

Although we know many sequence-specific transcription factors (TFs), how the DNA sequence of cis-regulatory elements is decoded and orchestrated on the genome scale to determine immune cell differentiation is beyond our grasp. Leveraging a granular atlas of chromatin accessibility across 81 immune cell types, we asked if a convolutional neural network (CNN) could learn to infer cell type-specific chromatin accessibility solely from regulatory DNA sequences. With a tailored architecture and an ensemble approach to CNN parameter interpretation, we show that our trained network ("AI-TAC") does so by rediscovering ab initio the binding motifs for known regulators and some unknown ones. Motifs whose importance is learned virtually as functionally important overlap strikingly well with positions determined by chromatin immunoprecipitation for several TFs. AI-TAC establishes a hierarchy of TFs and their interactions that drives lineage specification and also identifies stage-specific interactions, like Pax5/Ebf1 vs. Pax5/Prdm1, or the role of different NF-κB dimers in different cell types. AI-TAC assigns Spi1/Cebp and Pax5/Ebf1 as the drivers necessary for myeloid and B lineage fates, respectively, but no factors seemed as dominantly required for T cell differentiation, which may represent a fall-back pathway. Mouse-trained AI-TAC can parse human DNA, revealing a strikingly similar ranking of influential TFs and providing additional support that AI-TAC is a generalizable regulatory sequence decoder. Thus, deep learning can reveal the regulatory syntax predictive of the full differentiative complexity of the immune system.


Assuntos
Aprendizado Profundo , Hematopoese/genética , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição , Animais , Cromatina/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Fatores de Transcrição/química , Fatores de Transcrição/genética
10.
Nat Commun ; 11(1): 4483, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32900993

RESUMO

The Drosophila lymph gland, the larval hematopoietic organ comprised of prohemocytes and mature hemocytes, has been a valuable model for understanding mechanisms underlying hematopoiesis and immunity. Three types of mature hemocytes have been characterized in the lymph gland: plasmatocytes, lamellocytes, and crystal cells, which are analogous to vertebrate myeloid cells, yet molecular underpinnings of the lymph gland hemocytes have been less investigated. Here, we use single-cell RNA sequencing to comprehensively analyze heterogeneity of developing hemocytes in the lymph gland, and discover previously undescribed hemocyte types including adipohemocytes, stem-like prohemocytes, and intermediate prohemocytes. Additionally, we identify the developmental trajectory of hemocytes during normal development as well as the emergence of the lamellocyte lineage following active cellular immunity caused by wasp infestation. Finally, we establish similarities and differences between embryonically derived- and larval lymph gland hemocytes. Altogether, our study provides detailed insights into the hemocyte development and cellular immune responses at single-cell resolution.


Assuntos
Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Hemócitos/citologia , Hemócitos/metabolismo , Transcriptoma , Animais , Animais Geneticamente Modificados , Diferenciação Celular/genética , Linhagem da Célula/genética , Drosophila melanogaster/metabolismo , Ectoparasitoses/genética , Ectoparasitoses/metabolismo , Ectoparasitoses/patologia , Perfilação da Expressão Gênica , Hematopoese/genética , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/fisiologia , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Tecido Linfoide/parasitologia , RNA-Seq , Análise de Célula Única , Vespas/patogenicidade
11.
Proc Natl Acad Sci U S A ; 117(34): 20729-20740, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32796104

RESUMO

Tissue-resident macrophages can originate from embryonic or adult hematopoiesis. They play important roles in a wide range of biological processes including tissue remodeling during organogenesis, organ homeostasis, repair following injury, and immune response to pathogens. Although the origins and tissue-specific functions of resident macrophages have been extensively studied in many other tissues, they are not well characterized in skeletal muscle. In the present study, we have characterized the ontogeny of skeletal muscle-resident macrophages by lineage tracing and bone marrow transplant experiments. We demonstrate that skeletal muscle-resident macrophages originate from both embryonic hematopoietic progenitors located within the yolk sac and fetal liver as well as definitive hematopoietic stem cells located within the bone marrow of adult mice. Single-cell-based transcriptome analyses revealed that skeletal muscle-resident macrophages are distinctive from resident macrophages in other tissues as they express a distinct complement of transcription factors and are composed of functionally diverse subsets correlating to their origins. Functionally, skeletal muscle-resident macrophages appear to maintain tissue homeostasis and promote muscle growth and regeneration.


Assuntos
Macrófagos/imunologia , Músculo Esquelético/imunologia , Animais , Medula Óssea/metabolismo , Transplante de Medula Óssea/métodos , Diferenciação Celular/genética , Linhagem da Célula/genética , Desenvolvimento Embrionário , Feminino , Heterogeneidade Genética , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Homeostase , Macrófagos/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Organogênese/genética
12.
Gene ; 760: 145020, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32755656

RESUMO

Conserved sequences across species have always provided valuable insights to improve our understanding on the human genome's entity and the interplay among different loci. Lymphoma/leukemia related factor (LRF) is encoded by ZBTB7A gene and belongs to an evolutionarily conserved family of transcription factors, implicated in vital cellular functions. The present data, demonstrating the wide-spread and the high overlap of the LRF/ZBTB7A recognition sites with genomic segments identified as CpG islands in the human genome, suggest that its binding capacity strongly depends on a specific sequence-encoded feature within CpGs. We have previously shown that de-methylation of the CpG island 326 lying in the ZBTB7A gene promoter is associated with impaired pharmacological induction of fetal hemoglobin in ß-type hemoglobinopathies patients. Within this context we aimed to investigate the extent of the LRF/ZBTB7A conservation among primates and mouse genome, focusing our interest also on the CpG island flanking the gene's promoter region, in an effort to further establish its epigenetic regulatory role in human hematopoiesis and pharmacological involvement in hematopoietic disorders. Comparative analysis of the human ZBTB7A nucleotide and amino acid sequences and orthologous sequences among non-human primates and mouse, exhibited high conservation scores. Pathway analysis, clearly indicated that LRF/ZBTB7A influences conserved cellular processes. These data in conjunction with the high levels of expression foremost in hematopoietic tissues, highlighted LRF/ZBTB7A as an essential factor operating indisputably during hematopoiesis.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Doenças Hematológicas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Sequência Conservada/genética , Ilhas de CpG/genética , Bases de Dados Genéticas , Hemoglobina Fetal/genética , Hematopoese/genética , Humanos , Camundongos , Primatas/genética , Regiões Promotoras Genéticas/genética
13.
Proc Natl Acad Sci U S A ; 117(29): 17041-17048, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632001

RESUMO

A central task in developmental biology is to learn the sequence of fate decisions that leads to each mature cell type in a tissue or organism. Recently, clonal labeling of cells using DNA barcodes has emerged as a powerful approach for identifying cells that share a common ancestry of fate decisions. Here we explore the idea that stochasticity of cell fate choice during tissue development could be harnessed to read out lineage relationships after a single step of clonal barcoding. By considering a generalized multitype branching process, we determine the conditions under which the final distribution of barcodes over observed cell types encodes their bona fide lineage relationships. We then propose a method for inferring the order of fate decisions. Our theory predicts a set of symmetries of barcode covariance that serves as a consistency check for the validity of the method. We show that broken symmetries may be used to detect multiple paths of differentiation to the same cell types. We provide computational tools for general use. When applied to barcoding data in hematopoiesis, these tools reconstruct the classical hematopoietic hierarchy and detect couplings between monocytes and dendritic cells and between erythrocytes and basophils that suggest multiple pathways of differentiation for these lineages.


Assuntos
Linhagem da Célula , Código de Barras de DNA Taxonômico/métodos , Animais , Linhagem da Célula/genética , Linhagem da Célula/fisiologia , Árvores de Decisões , Células Dendríticas/citologia , Eritrócitos/citologia , Hematopoese/genética , Hematopoese/fisiologia , Leucócitos/citologia , Modelos Biológicos , Biologia de Sistemas
14.
Nat Commun ; 11(1): 3327, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620863

RESUMO

Gaucher disease is a lysosomal storage disorder caused by insufficient glucocerebrosidase activity. Its hallmark manifestations are attributed to infiltration and inflammation by macrophages. Current therapies for Gaucher disease include life-long intravenous administration of recombinant glucocerebrosidase and orally-available glucosylceramide synthase inhibitors. An alternative approach is to engineer the patient's own hematopoietic system to restore glucocerebrosidase expression, thereby replacing the affected cells, and constituting a potential one-time therapy for this disease. Here, we report an efficient CRISPR/Cas9-based approach that targets glucocerebrosidase expression cassettes with a monocyte/macrophage-specific element to the CCR5 safe-harbor locus in human hematopoietic stem and progenitor cells. The targeted cells generate glucocerebrosidase-expressing macrophages and maintain long-term repopulation and multi-lineage differentiation potential with serial transplantation. The combination of a safe-harbor and a lineage-specific promoter establishes a universal correction strategy and circumvents potential toxicity of ectopic glucocerebrosidase in the stem cells. Furthermore, it constitutes an adaptable platform for other lysosomal enzyme deficiencies.


Assuntos
Edição de Genes/métodos , Glucosilceramidase/metabolismo , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/enzimologia , Macrófagos/enzimologia , Monócitos/enzimologia , Animais , Diferenciação Celular/genética , Células Cultivadas , Doença de Gaucher/genética , Doença de Gaucher/terapia , Glucosilceramidase/genética , Células HEK293 , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos , Macrófagos/metabolismo , Engenharia Metabólica , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Monócitos/metabolismo , Transplante Autólogo
15.
Ann Hematol ; 99(10): 2231-2242, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32621182

RESUMO

Long non-coding RNAs (lncRNAs) have an established role in cell biology. Among their functions is the regulation of hematopoiesis. They characterize the different stages of hematopoiesis in a more lineage-restricted expression pattern than coding mRNAs. They affect hematopoietic stem cell renewal, proliferation, and differentiation of committed progenitors by interacting with master regulators transcription factors. Among these transcription factors, MYC has a prominent role. Similar to MYC's transcriptional activation/amplification of protein coding genes, MYC also regulates lncRNAs' expression profile, while it is also regulated by lncRNAs. Both myeloid and lymphoid malignancies are prone to the association of MYC with lncRNAs. Such interaction inhibits apoptosis, enhances cell proliferation, deregulates metabolism, and promotes genomic instability and resistance to treatment. In this review, we discuss the recent findings that encompass the crosstalk between lncRNAs and describe the pathways that very probably have a pathogenetic role in both acute and chronic hematologic malignancies.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hematológicas/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/fisiologia , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Autorrenovação Celular/genética , Genes myc , Hematopoese/genética , Humanos , Leucemia/genética , Linfócitos/metabolismo , Linfócitos/patologia , Linfoma/genética , Mieloma Múltiplo/genética , Células Mieloides/metabolismo , Células Mieloides/patologia , Nicho de Células-Tronco
16.
Gene ; 758: 144966, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32687945

RESUMO

RAD21 (also known as KIAA0078, NXP1, HR21, Mcd1, Scc1, and hereafter called RAD21), an essential gene, encodes a DNA double-strand break (DSB) repair protein that is evolutionarily conserved in all eukaryotes from budding yeast to humans. RAD21 protein is a structural component of the highly conserved cohesin complex consisting of RAD21, SMC1a, SMC3, and SCC3 [STAG1 (SA1) and STAG2 (SA2) in metazoans] proteins, involved in sister chromatid cohesion. This function is essential for proper chromosome segregation, post-replicative DNA repair, and prevention of inappropriate recombination between repetitive regions. In interphase, cohesin also functions in the control of gene expression by binding to numerous sites within the genome. In addition to playing roles in the normal cell cycle and DNA DSB repair, RAD21 is also linked to the apoptotic pathways. Germline heterozygous or homozygous missense mutations in RAD21 have been associated with human genetic disorders, including developmental diseases such as Cornelia de Lange syndrome (CdLS) and chronic intestinal pseudo-obstruction (CIPO) called Mungan syndrome, respectively, and collectively termed as cohesinopathies. Somatic mutations and amplification of the RAD21 have also been widely reported in both human solid and hematopoietic tumors. Considering the role of RAD21 in a broad range of cellular processes that are hot spots in neoplasm, it is not surprising that the deregulation of RAD21 has been increasingly evident in human cancers. Herein, we review the biology of RAD21 and the cellular processes that this important protein regulates and discuss the significance of RAD21 deregulation in cancer and cohesinopathies.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Neoplasias/genética , Apoptose/genética , Esôfago de Barrett/genética , Quebras de DNA de Cadeia Dupla , Síndrome de Cornélia de Lange/genética , Hematopoese/genética , Humanos , Pseudo-Obstrução Intestinal/genética , Meiose/genética , Neoplasias/patologia
17.
Nature ; 584(7819): 136-141, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581363

RESUMO

Clonally expanded blood cells that contain somatic mutations (clonal haematopoiesis) are commonly acquired with age and increase the risk of blood cancer1-9. The blood clones identified so far contain diverse large-scale mosaic chromosomal alterations (deletions, duplications and copy-neutral loss of heterozygosity (CN-LOH)) on all chromosomes1,2,5,6,9, but the sources of selective advantage that drive the expansion of most clones remain unknown. Here, to identify genes, mutations and biological processes that give selective advantage to mutant clones, we analysed genotyping data from the blood-derived DNA of 482,789 participants from the UK Biobank10. We identified 19,632 autosomal mosaic chromosomal alterations and analysed these for relationships to inherited genetic variation. We found 52 inherited, rare, large-effect coding or splice variants in 7 genes that were associated with greatly increased vulnerability to clonal haematopoiesis with specific acquired CN-LOH mutations. Acquired mutations systematically replaced the inherited risk alleles (at MPL) or duplicated them to the homologous chromosome (at FH, NBN, MRE11, ATM, SH2B3 and TM2D3). Three of the genes (MRE11, NBN and ATM) encode components of the MRN-ATM pathway, which limits cell division after DNA damage and telomere attrition11-13; another two (MPL and SH2B3) encode proteins that regulate the self-renewal of stem cells14-16. In addition, we found that CN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote the expansion of haematopoietic cells to replace their homologous (allelic) counterparts, increasing polygenic drive for blood-cell proliferation traits. Readily acquired mutations that replace chromosomal segments with their homologous counterparts seem to interact with pervasive inherited variation to create a challenge for lifelong cytopoiesis.


Assuntos
Evolução Clonal/genética , Células Clonais/metabolismo , Hematopoese/genética , Herança Multifatorial/genética , Adulto , Idoso , Alelos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Divisão Celular/genética , Aberrações Cromossômicas , Células Clonais/citologia , Células Clonais/patologia , Feminino , Predisposição Genética para Doença , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Perda de Heterozigosidade/genética , Masculino , Pessoa de Meia-Idade , Mosaicismo , Reino Unido
18.
Nature ; 584(7819): 130-135, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581364

RESUMO

The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers1-10. Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN, MRE11 and CTU2 (odds ratio, 28-91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted.


Assuntos
Envelhecimento/genética , Aberrações Cromossômicas , Cromossomos Humanos/genética , Células Clonais/metabolismo , Genoma Humano/genética , Células-Tronco Hematopoéticas/metabolismo , Mutação , Idoso de 80 Anos ou mais , Alelos , Linhagem da Célula , Células Clonais/citologia , Células Clonais/patologia , Estudos de Coortes , Feminino , Loci Gênicos/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/patologia , Humanos , Japão , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia de Células T/genética , Leucemia de Células T/patologia , Masculino , Mosaicismo , Reino Unido
19.
Am J Hum Genet ; 107(2): 325-329, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574563

RESUMO

Large copy-number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e., germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed for detecting mosaic variants. We found 160 individuals that carry >10 Mb copy number changes, including 56 with whole chromosome aneuploidies. Nineteen (12%) individuals had a diagnosis of Down syndrome or other developmental disorder, while 84 (52.5%) individuals had a diagnosis of hematological malignancies or chronic myeloproliferative disorders. Notably, there was no evidence of mosaicism in the blood for many of these large CNVs, so they could easily be mistaken for germline alleles even when caused by somatic mutations. We therefore suggest that somatic mutations associated with blood cancers may result in false estimates of rare variant penetrance from population biobanks.


Assuntos
Variações do Número de Cópias de DNA/genética , Hematopoese/genética , Adulto , Idoso , Alelos , Aneuploidia , Bancos de Espécimes Biológicos , Cromossomos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Mutação/genética , Penetrância , Reino Unido
20.
Leukemia ; 34(10): 2660-2672, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32518416

RESUMO

We sought to determine the significance of myeloid clonal hematopoiesis (CH) in the UK Biobank cohort (n = 502,524, median age = 58 years). Utilizing SNP array (n = 486,941) and whole exome sequencing data (n = 49,956), we identified 1166 participants with myeloid CH, defined by myeloid-associated mosaic chromosome abnormalities (mCA) and/or likely somatic driver mutations in DNMT3A, TET2, ASXL1, JAK2, SRSF2, or PPM1D. Myeloid CH increased by 1.1-fold per annum (myeloid mCA, P = 1.57 × 10-38; driver mutations, P = 5.89 × 10-47). Genome-wide association analysis identified two distinct signals within TERT that predisposed to myeloid CH, plus a weaker signal corresponding to the JAK2 46/1 haplotype. Specific subtypes of myeloid CH were associated with several blood features and clinical phenotypes, including TET2 mutations and chronic obstructive pulmonary disease. Smoking history was significantly associated with myeloid CH: 53% of myeloid CH cases were smokers compared to 44% of controls (P = 3.38 × 10-6), a difference principally due to current (OR = 1.10; P = 6.14 × 10-6) rather than past smoking (P = 0.08). Breakdown of CH by specific mutation type revealed that ASXL1 loss of function mutations were most strongly associated with current smoking status (OR = 1.07; P = 1.92 × 10-5), and the only abnormality associated with past smoking (OR = 1.04; P = 0.0026). We suggest that the inflammatory environment induced by smoking may promote the outgrowth of ASXL1-mutant clones.


Assuntos
Mutação/genética , Mielopoese/genética , Proteínas Repressoras/genética , Fumar/genética , Bancos de Espécimes Biológicos , Aberrações Cromossômicas , Células Clonais , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla/métodos , Hematopoese/genética , Humanos , Masculino , Pessoa de Meia-Idade , Reino Unido
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