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1.
Acta Neuropathol Commun ; 12(1): 3, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167174

RESUMO

Alzheimer's Disease (AD) is a disorder characterized by cognitive decline, neurodegeneration, and accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. Dysregulation of epigenetic histone modifications may lead to expression of transcriptional programs that play a role either in protecting against disease genesis or in worsening of disease pathology. One such histone modification, acetylation of histone H3 lysine residue 27 (H3K27ac), is primarily localized to genomic enhancer regions and promotes active gene transcription. We previously discovered H3K27ac to be more abundant in AD patient brain tissue compared to the brains of age-matched non-demented controls. In this study, we use iPSC-neurons derived from familial AD patients with an amyloid precursor protein (APP) duplication (APPDup neurons) as a model to study the functional effect of lowering CBP/P300 enzymes that catalyze H3K27ac. We found that homeostatic amyloid-reducing genes were upregulated in the APPDup neurons compared to non-demented controls. We lowered CBP/P300 to reduce H3K27ac, which led to decreased expression of numerous of these homeostatic amyloid-reducing genes, along with increased extracellular secretion of a toxic amyloid-ß species, Aß(1-42). Our findings suggest that epigenomic histone acetylation, including H3K27ac, drives expression of compensatory genetic programs in response to AD-associated insults, specifically those resulting from APP duplication, and thus may play a role in mitigating AD pathology in neurons.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Histonas/genética , Acetilação , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloide/metabolismo , Proteínas tau/metabolismo
2.
Nat Aging ; 3(4): 402-417, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37117791

RESUMO

Mammalian aging is characterized by the progressive loss of tissue function and increased risk for disease. Accumulation of senescent cells in aging tissues partly contributes to this decline, and targeted depletion of senescent cells in vivo ameliorates many age-related phenotypes. The fundamental molecular mechanisms responsible for the decline of cellular health and fitness during senescence and aging are largely unknown. In this study, we investigated whether chromatin-mediated loss of transcriptional fidelity, known to contribute to fitness and survival in yeast and worms, also occurs during human cellular senescence and mouse aging. Our findings reveal aberrant transcription initiation inside genes during senescence and aging that co-occurs with changes in the chromatin landscape. Interventions that alter these spurious transcripts have profound consequences on cellular health, primarily affecting intracellular signal transduction pathways. We propose that age-related spurious transcription promotes a noisy transcriptome and degradation of coherent transcriptional networks.


Assuntos
Envelhecimento , Senescência Celular , Humanos , Animais , Camundongos , Envelhecimento/genética , Senescência Celular/genética , Cromatina/genética , Transcriptoma , Fenótipo , Mamíferos/genética
3.
Nat Struct Mol Biol ; 30(1): 31-37, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36536103

RESUMO

To determine how different pioneer transcription factors form a targeted, accessible nucleosome within compacted chromatin and collaborate with an ATP-dependent chromatin remodeler, we generated nucleosome arrays in vitro with a central nucleosome containing binding sites for the hematopoietic E-Twenty Six (ETS) factor PU.1 and Basic Leucine Zipper (bZIP) factors C/EBPα and C/EBPß. Our long-read sequencing reveals that each factor can expose a targeted nucleosome on linker histone-compacted arrays, but with different nuclease sensitivity patterns. The DNA binding domain of PU.1 binds mononucleosomes, but requires an additional intrinsically disordered domain to bind and open compacted chromatin. The canonical mammalian SWI/SNF (cBAF) remodeler was unable to act upon two forms of locally open chromatin unless cBAF was enabled by a separate transactivation domain of PU.1. cBAF potentiates the PU.1 DNA binding domain to weakly open chromatin in the absence of the PU.1 disordered domain. Our findings reveal a hierarchy by which chromatin is opened and show that pioneer factors can provide specificity for action by nucleosome remodelers.


Assuntos
Cromatina , Nucleossomos , Animais , Fatores de Transcrição/metabolismo , DNA , Trifosfato de Adenosina/metabolismo , Montagem e Desmontagem da Cromatina , Mamíferos/genética
4.
Sci Adv ; 8(3): eabj5688, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35061542

RESUMO

Histone acetylation is governed by nuclear acetyl-CoA pools generated, in part, from local acetate by metabolic enzyme acetyl-CoA synthetase 2 (ACSS2). We hypothesize that during gene activation, a local transfer of intact acetate occurs via sequential action of epigenetic and metabolic enzymes. Using stable isotope labeling, we detect transfer between histone acetylation sites both in vitro using purified mammalian enzymes and in vivo using quiescence exit in Saccharomyces cerevisiae as a change-of-state model. We show that Acs2, the yeast ortholog of ACSS2, is recruited to chromatin during quiescence exit and observe dynamic histone acetylation changes proximal to Acs2 peaks. We find that Acs2 is preferentially associated with the most up-regulated genes, suggesting that acetyl group transfer plays an important role in gene activation. Overall, our data reveal direct transfer of acetate between histone lysine residues to facilitate rapid transcriptional induction, an exchange that may be critical during changes in nutrient availability.

5.
Cell ; 184(25): 6081-6100.e26, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34861191

RESUMO

Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva/métodos , Neoplasias Pancreáticas/terapia , Receptores de Antígenos Quiméricos/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Proteínas Inibidoras de Diferenciação/imunologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Nus , Camundongos SCID , Proteínas de Neoplasias/imunologia , Fatores de Transcrição SOXC/imunologia
7.
STAR Protoc ; 2(3): 100651, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34485932

RESUMO

The protocol allows for labeling nascent RNA without isolating nuclei. The cell-permeable uridine analog, 5-ethynyluridine (EU), is added to media to allow in vivo labeling of nascent transcripts. Cells are lysed, total RNA is collected, and biotin is conjugated to EU-labeled RNAs. Custom biotin RNAs are added and biotinylated RNAs are isolated for generation of cDNA libraries. The sequencing data are normalized to controls for quantitative assessment of the nascent transcriptome. The protocol takes 4 days, not including sequencing and analysis. For complete details on the use and execution of this protocol, please refer to Palozola et al. (2017).


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Biologia Molecular/métodos , RNA/química , Biotina/química , Linhagem Celular , Precipitação Química , Humanos , RNA/genética , RNA-Seq , Uridina/química
8.
Nat Cell Biol ; 23(8): 905-914, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34354237

RESUMO

Heterochromatin, typically marked by histone H3 trimethylation at lysine 9 (H3K9me3) or lysine 27 (H3K27me3), represses different protein-coding genes in different cells, as well as repetitive elements. The basis for locus specificity is unclear. Previously, we identified 172 proteins that are embedded in sonication-resistant heterochromatin (srHC) harbouring H3K9me3. Here, we investigate in humans how 97 of the H3K9me3-srHC proteins repress heterochromatic genes. We reveal four groups of srHC proteins that each repress many common genes and repeat elements. Two groups repress H3K9me3-embedded genes with different extents of flanking srHC, one group is specific for srHC genes with H3K9me3 and H3K27me3, and one group is specific for genes with srHC as the primary feature. We find that the enhancer of rudimentary homologue (ERH) is conserved from Schizosaccharomyces pombe in repressing meiotic genes and, in humans, now represses other lineage-specific genes and repeat elements. The study greatly expands our understanding of H3K9me3-based gene repression in vertebrates.


Assuntos
Proteínas Cromossômicas não Histona/fisiologia , Regulação da Expressão Gênica , Heterocromatina/fisiologia , Células Cultivadas , Sequência Conservada , Células Hep G2 , Histonas/metabolismo , Humanos
9.
Mol Cancer Res ; 19(11): 1854-1867, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34330844

RESUMO

Previous transcriptome studies of human pancreatic ductal adenocarcinoma (PDAC) compare non-cancerous pancreatic intraepithelial neoplasias (PanIN) with late-stage PDAC obtained from different patients, thus have limited ability to discern network dynamics that contribute to the disease progression. We demonstrated previously that the 10-22 cell line, an induced pluripotent stem cell-like line reprogrammed from late-stage human PDAC cells, recapitulated the progression from PanINs to PDAC upon transplantation into NOD/LtSz-scid/IL2R-gammanull mice. Herein, we investigated the transition from precursor to PDAC using the isogenic model. We analyzed transcriptomes of genetically tagged 10-22 cells progressing from PanINs to PDAC in mice and validated the results using The Cancer Genome Atlas PDAC dataset, human clinical PanIN and PDAC tissues, and a well-established murine PDAC model. We functionally studied candidate proteins using human normal (H6C7) and cancerous (Miapaca2, Aspc1) pancreatic ductal epithelial cell lines. 10-22 cell-derived PDAC displayed the molecular signature of clinical human PDAC. Expression changes of many genes were transient during PDAC progression. Pathways for extracellular vesicle transport and neuronal cell differentiation were derepressed in the progression of PanINs to PDAC. HMG-box transcription factor 1 (HBP1) and BTB domain and CNC homolog 1 (BACH1) were implicated in regulating dynamically expressed genes during PDAC progression, and their expressions inversely correlated with PDAC patients' prognosis. Ectopic expression of HBP1 increased proliferation and migration of normal and cancerous pancreatic cells, indicating that HBP1 may confer the cell dissemination capacity in early PDAC progression. This unique longitudinal analysis provides insights into networks underlying human PDAC progression and pathogenesis. IMPLICATIONS: Manipulation of HBP1, BACH1, and RUN3 networks during PDAC progression can be harnessed to develop new targets for treating PDAC.


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Transcriptoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Progressão da Doença , Humanos , Estudos Longitudinais , Camundongos , Análise de Sobrevida
10.
Dev Cell ; 56(5): 602-612.e4, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33636105

RESUMO

Tissue-specific DNA methylation patterns are created by transcription factors that recruit methylation and demethylation enzymes to cis-regulatory elements. To date, it is not known whether transcription factors are needed to continuously maintain methylation profiles in development and mature tissues or whether they only establish these marks during organ development. We queried the role of the pioneer factor FoxA in generating hypomethylated DNA at liver enhancers. We discovered a set of FoxA-binding sites that undergo regional, FoxA-dependent demethylation during organ development. Conditional ablation of FoxA genes in the adult liver demonstrated that continued FoxA presence was not required to maintain the hypomethylated state, even when massive cell proliferation was induced. This study provides strong evidence for the stable, epigenetic nature of tissue-specific DNA methylation patterns directed by lineage-determining transcription factors during organ development.


Assuntos
Diferenciação Celular , Metilação de DNA , Elementos Facilitadores Genéticos , Epigênese Genética , Fator 3-alfa Nuclear de Hepatócito/fisiologia , Fator 3-beta Nuclear de Hepatócito/fisiologia , Fígado/metabolismo , Animais , Sítios de Ligação , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Desmetilação , Regulação da Expressão Gênica no Desenvolvimento , Fígado/embriologia , Masculino , Camundongos , Camundongos Knockout
11.
Sci Adv ; 6(49)2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33277249

RESUMO

Here, we selectively target pancreatic ductal adenocarcinoma (PDAC) cells harboring a hemizygous gene essential for cell growth. MYB binding protein 1A (MYBBP1A), encoding a chromatin-bound protein, is hemizygous in most of the PDAC due to a chromosome 17p deletion that also spans TP53 We find that hemizygous MYBBP1A loss in isogenic PDAC cells promotes tumorigenesis but, paradoxically, homozygous MYBBP1A loss is associated with impaired cell growth and decreased tumorigenesis. Poly-adenosine 5'-diphosphate-ribose polymerase 1 (PARP1) interacts with MYBBP1A and displaces it from chromatin. Small molecules, such as olaparib, that trap PARP1 to chromatin are able to evict the minimal pool of chromatin-bound MYBBP1A protein in MYBBP1A hemizygous cells and impair cell growth, greater than its impact on wild-type cells. Our findings reveal how a cell essential gene with one allele lost in cancer cells can be preferentially susceptible to a specific molecular therapy, when compared to wild-type cells.

13.
Nat Genet ; 52(10): 1024-1035, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32989324

RESUMO

Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer's disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-ß42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin-gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.


Assuntos
Doença de Alzheimer/genética , Agregação Patológica de Proteínas/genética , Proteoma/genética , Transcriptoma/genética , Acetilação , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Cromatina/genética , Epigenoma/genética , Histona Acetiltransferases/genética , Código das Histonas/genética , Histonas/genética , Humanos , Fragmentos de Peptídeos/genética , Agregação Patológica de Proteínas/patologia , Transdução de Sinais/genética , Ativação Transcricional/genética
14.
Nat Genet ; 52(4): 418-427, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203463

RESUMO

Gene network transitions in embryos and other fate-changing contexts involve combinations of transcription factors. A subset of fate-changing transcription factors act as pioneers; they scan and target nucleosomal DNA and initiate cooperative events that can open the local chromatin. However, a gap has remained in understanding how molecular interactions with the nucleosome contribute to the chromatin-opening phenomenon. Here we identified a short α-helical region, conserved among FOXA pioneer factors, that interacts with core histones and contributes to chromatin opening in vitro. The same domain is involved in chromatin opening in early mouse embryos for normal development. Thus, local opening of chromatin by interactions between pioneer factors and core histones promotes genetic programming.


Assuntos
Redes Reguladoras de Genes/genética , Histonas/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Linhagem Celular , Cromatina/genética , DNA/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Nucleossomos/genética , Transcrição Gênica/genética
15.
Dev Cell ; 51(6): 745-758.e6, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31761669

RESUMO

During mammalian spermatogenesis, germ cell chromatin undergoes dramatic histone acetylation-mediated reorganization, whereby 90%-99% of histones are evicted. Given the potential role of retained histones in fertility and embryonic development, the genomic location of retained nucleosomes is of great interest. However, the ultimate position and mechanisms underlying nucleosome eviction or retention are poorly understood, including several studies utilizing micrococcal-nuclease sequencing (MNase-seq) methodologies reporting remarkably dissimilar locations. We utilized assay for transposase accessible chromatin sequencing (ATAC-seq) in mouse sperm and found nucleosome enrichment at promoters but also retention at inter- and intragenic regions and repetitive elements. We further generated germ-cell-specific, conditional knockout mice for the key histone acetyltransferase Gcn5, which resulted in abnormal chromatin dynamics leading to increased sperm histone retention and severe reproductive phenotypes. Our findings demonstrate that Gcn5-mediated histone acetylation promotes chromatin accessibility and nucleosome eviction in spermiogenesis and that loss of histone acetylation leads to defects that disrupt male fertility and potentially early embryogenesis.


Assuntos
Histonas/metabolismo , Nucleossomos/metabolismo , Espermatogênese/fisiologia , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Animais , Cromatina/metabolismo , Masculino , Camundongos , Regiões Promotoras Genéticas/genética , Processamento de Proteína Pós-Traducional/fisiologia , Espermatozoides/metabolismo
16.
Nature ; 571(7764): 211-218, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207603

RESUMO

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Epistasia Genética , Proteínas de Homeodomínio/metabolismo , Transcrição Gênica , Animais , Calcineurina/metabolismo , Sinalização do Cálcio , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica/imunologia , Genótipo , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Evasão Tumoral
17.
Mol Cell ; 73(4): 684-698.e8, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30773298

RESUMO

Accumulation of senescent cells during aging contributes to chronic inflammation and age-related diseases. While senescence is associated with profound alterations of the epigenome, a systematic view of epigenetic factors in regulating senescence is lacking. Here, we curated a library of short hairpin RNAs for targeted silencing of all known epigenetic proteins and performed a high-throughput screen to identify key candidates whose downregulation can delay replicative senescence of primary human cells. This screen identified multiple new players including the histone acetyltransferase p300 that was found to be a primary driver of the senescent phenotype. p300, but not the paralogous CBP, induces a dynamic hyper-acetylated chromatin state and promotes the formation of active enhancer elements in the non-coding genome, leading to a senescence-specific gene expression program. Our work illustrates a causal role of histone acetyltransferases and acetylation in senescence and suggests p300 as a potential therapeutic target for senescence and age-related diseases.


Assuntos
Proliferação de Células , Senescência Celular , Montagem e Desmontagem da Cromatina , Cromatina/enzimologia , Fibroblastos/enzimologia , Histonas/metabolismo , Processamento de Proteína Pós-Traducional , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Proliferação de Células/genética , Senescência Celular/genética , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Repressão Epigenética , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Histonas/genética , Humanos , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fatores de Tempo , Transcrição Gênica , Fatores de Transcrição de p300-CBP/genética
18.
Science ; 363(6424): 294-297, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30606806

RESUMO

Gene silencing by chromatin compaction is integral to establishing and maintaining cell fates. Trimethylated histone 3 lysine 9 (H3K9me3)-marked heterochromatin is reduced in embryonic stem cells compared to differentiated cells. However, the establishment and dynamics of closed regions of chromatin at protein-coding genes, in embryologic development, remain elusive. We developed an antibody-independent method to isolate and map compacted heterochromatin from low-cell number samples. We discovered high levels of compacted heterochromatin, H3K9me3-decorated, at protein-coding genes in early, uncommitted cells at the germ-layer stage, undergoing profound rearrangements and reduction upon differentiation, concomitant with cell type-specific gene expression. Perturbation of the three H3K9me3-related methyltransferases revealed a pivotal role for H3K9me3 heterochromatin during lineage commitment at the onset of organogenesis and for lineage fidelity maintenance.


Assuntos
Diferenciação Celular , Linhagem da Célula , Células-Tronco Embrionárias/citologia , Heterocromatina/genética , Histonas/química , Animais , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Inativação Gênica , Camadas Germinativas/citologia , Hepatócitos/citologia , Células Secretoras de Insulina/citologia , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Organogênese
19.
Gastroenterology ; 156(6): 1834-1848, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30689973

RESUMO

BACKGROUND & AIMS: Little is known about mechanisms that underlie postnatal hepatocyte maturation and fibrosis at the chromatin level. We investigated the transcription of genes involved in maturation and fibrosis in postnatal hepatocytes of mice, focusing on the chromatin compaction the roles of the Polycomb repressive complex 2 histone methyltransferases EZH1 and EZH2. METHODS: Hepatocytes were isolated from mixed background C57BL/6J-C3H mice, as well as mice with liver-specific disruption of Ezh1 and/or Ezh2, at postnatal day 14 and 2 months after birth. Liver tissues were collected and analyzed by RNA sequencing, H3K27me3 chromatin immunoprecipitation sequencing, and sonication-resistant heterochromatin sequencing (a method to map heterochromatin and euchromatin). Liver damage was characterized by histologic analysis. RESULTS: We found more than 3000 genes differentially expressed in hepatocytes during liver maturation from postnatal day 14 to month 2 after birth. Disruption of Ezh1 and Ezh2 in livers caused perinatal hepatocytes to differentiate prematurely and to express genes at postnatal day 14 that would normally be induced by month 2 and differentiate prematurely. Loss of Ezh1 and Ezh2 also resulted in liver fibrosis. Genes with H3K27me3-postive and H3K4me3-positive euchromatic promoters were prematurely induced in hepatocytes with loss of Ezh1 and Ezh2-these genes included those that regulate hepatocyte maturation, fibrosis, and genes not specifically associated with the liver lineage. CONCLUSIONS: The Polycomb repressive complex 2 proteins EZH1 and EZH2 regulate genes that control hepatocyte maturation and fibrogenesis and genes not specifically associated with the liver lineage by acting at euchromatic promoter regions. EZH1 and EZH2 thereby promote liver homeostasis and prevent liver damage. Strategies to manipulate Polycomb proteins might be used to improve hepatocyte derivation protocols or developed for treatment of patients with liver fibrosis.


Assuntos
Diferenciação Celular/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Repressão Epigenética , Regulação da Expressão Gênica/genética , Cirrose Hepática/genética , Complexo Repressor Polycomb 2/genética , Animais , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Eucromatina , Feminino , Expressão Gênica , Ontologia Genética , Hepatócitos , Histonas/metabolismo , Cirrose Hepática/patologia , Masculino , Metilação , Camundongos , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , Fatores de Tempo
20.
Nat Neurosci ; 21(4): 497-505, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29507413

RESUMO

Aging is the strongest risk factor for Alzheimer's disease (AD), although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compare the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls. We found that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes with distinctive functional roles. Furthermore, we discovered an association between the genomic locations of significant H4K16ac changes with genetic variants identified in prior AD genome-wide association studies and with expression quantitative trait loci. Our results establish the basis for an epigenetic link between aging and AD.


Assuntos
Envelhecimento , Doença de Alzheimer , Encéfalo/patologia , Epigênese Genética/fisiologia , Epigenômica/métodos , Histona Desacetilase 1/metabolismo , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Análise de Variância , Encéfalo/metabolismo , Imunoprecipitação da Cromatina , Feminino , Estudo de Associação Genômica Ampla , Histona Desacetilase 1/genética , Humanos , Masculino , Pessoa de Meia-Idade
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