H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity

AbstractThe developmental role of histone H3K9 methylation (H3K9me), which typifies heterochromatin, remains unclear. In Caenorhabditis elegans, loss of H3K9me leads to a highly divergent upregulation of genes with tissue and developmental-stage specificity. During development H3K9me is lost from differentiated cell type-specific genes and gained at genes expressed in earlier developmental stages or other tissues. The continuous deposition of H3K9me2 by the SETDB1 homolog MET-2 after terminal differentiation is necessary to maintain repression. In differentiated tissues, H3K9me ensures silencing by restricting the activity of a defined set of transcription factors at promoters and enhancers. Increased chromatin accessibility following the loss of H3K9me is neither sufficient nor necessary to drive transcription. Increased ATAC-seq signal and gene expression correlate at a subset of loci positioned away from the nuclear envelope, while derepressed genes at the nuclear periphery remain poorly accessible despite being transcribed. In conclusion, H3K9me deposition can confer tissue-specific gene expression and maintain the integrity of terminally differentiated muscle by restricting transcription factor activity.

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Enhancer dependence of cell-type–specific gene expression increases with developmental age

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2008672117 ◽

2020 ◽

Vol 117 (35) ◽

pp. 21450-21458 ◽

Cited By ~ 1

Author(s):

Wenqing Cai ◽

Jialiang Huang ◽

Qian Zhu ◽

Bin E. Li ◽

Davide Seruggia ◽

...

Keyword(s):

Gene Expression ◽

Developmental Stages ◽

Three Dimensional ◽

Chromatin Accessibility ◽

Specific Gene ◽

Embryonic Cells ◽

Cell Type ◽

Cell Type Specific ◽

Specific Regulation ◽

Highly Correlated

How overall principles of cell-type–specific gene regulation (the “logic”) may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic, and three-dimensional (3D) genomic profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1, and Myb occupancy. EryP-/EryD-shared enhancers are highly correlated with red blood cell identity genes, whereas cell-type–specific regulation employs differentciselements in EryP and EryD cells. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes rely more on distal enhancers for regulation involving Myb-mediated enhancer activation. Gata1 HiChIP demonstrated an overall increased enhancer–promoter interactions at EryD-specific genes, whereas genome editing in selected loci confirmed distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer dependence of transcription, we observed a progressive reliance on cell-specific enhancers with increasing ontogenetic age among diverse tissues of mouse and human origin. Our findings highlight fundamental and conserved differences at distinct developmental stages, characterized by simpler promoter-centric regulation of cell-type–specific genes in embryonic cells and increased combinatorial enhancer-driven control in adult cells.

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S1.4 The transcription factor Hand2 is necessary for differentiation and cell type-specific gene expression of sympathetic and enteric neurons in murine embryos

Autonomic Neuroscience ◽

10.1016/j.autneu.2009.05.009 ◽

2009 ◽

Vol 149 (1-2) ◽

pp. 20-21

Author(s):

T.J. Hendershot ◽

J. Liu ◽

S. Lin ◽

M.J. Howard

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Enteric Neurons ◽

Specific Gene ◽

Cell Type ◽

Specific Gene Expression ◽

Cell Type Specific ◽

Murine Embryos

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Suppressive effects of transcription factor GATA-1 on cell type-specific gene expression in dendritic cells

Immunogenetics ◽

10.1007/s00251-010-0444-1 ◽

2010 ◽

Vol 62 (7) ◽

pp. 421-429 ◽

Cited By ~ 5

Author(s):

Naomi Shimokawa ◽

Chiharu Nishiyama ◽

Nobuhiro Nakano ◽

Keiko Maeda ◽

Ryuyo Suzuki ◽

...

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Transcription Factor ◽

Specific Gene ◽

Cell Type ◽

Specific Gene Expression ◽

Cell Type Specific

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Detecting differential transcription factor activity from ATAC-seq data

10.1101/315622 ◽

2018 ◽

Cited By ~ 2

Author(s):

Ignacio J. Tripodi ◽

Mary A. Allen ◽

Robin D. Dowell

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Chromatin Accessibility ◽

Open Chromatin ◽

Nucleotide Polymorphisms ◽

Transcription Factor Activity ◽

Factor Activity ◽

Genome Wide ◽

Recognition Motifs ◽

Differential Transcription

AbstractTranscription factors are managers of the cellular factory, and key components to many diseases. Many non-coding single nucleotide polymorphisms affect transcription factors, either by directly altering the protein or its functional activity at individual binding sites. Here we first briefly summarize high throughput approaches to studying transcription factor activity. We then demonstrate, using published chromatin accessibility data (specifically ATAC-seq), that the genome wide profile of TF recognition motifs relative to regions of open chromatin can determine the key transcription factor altered by a perturbation. Our method of determining which TF are altered by a perturbation is simple, quick to implement and can be used when biological samples are limited. In the future, we envision this method could be applied to determining which TFs show altered activity in response to a wide variety of drugs and diseases.

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Faculty Opinions recommendation of A protein activity assay to measure global transcription factor activity reveals determinants of chromatin accessibility.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733265726.793547241 ◽

2018 ◽

Author(s):

Lars Malmstroem

Keyword(s):

Transcription Factor ◽

Chromatin Accessibility ◽

Transcription Factor Activity ◽

Factor Activity ◽

Activity Assay ◽

Protein Activity

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Transcription factor mTEAD-2 is selectively expressed at the beginning of zygotic gene expression in the mouse

Development ◽

10.1242/dev.124.10.1963 ◽

1997 ◽

Vol 124 (10) ◽

pp. 1963-1973 ◽

Cited By ~ 4

Author(s):

K.J. Kaneko ◽

E.B. Cullinan ◽

K.E. Latham ◽

M.L. DePamphilis

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Cdna Library ◽

Northern Analysis ◽

Transcription Factor Activity ◽

Factor Activity ◽

Rt Pcr ◽

Mouse Development ◽

Adult Tissues ◽

Zygotic Gene

mTEF-1 is the prototype of a family of mouse transcription factors that share the same TEA DNA binding domain (mTEAD genes) and are widely expressed in adult tissues. At least one member of this family is expressed at the beginning of mouse development, because mTEAD transcription factor activity was not detected in oocytes, but first appeared at the 2-cell stage in development, concomitant with the onset of zygotic gene expression. Since embryos survive until day 11 in the absence of mTEAD-1 (TEF-1), another family member likely accounts for this activity. Screening an EC cell cDNA library yielded mTEAD-1, 2 and 3 genes. RT-PCR detected RNA from all three of these genes in oocytes, but upon fertilization, mTEAD-1 and 3 mRNAs disappeared. mTEAD-2 mRNA, initially present at approx. 5,000 copies per egg, decreased to approx. 2,000 copies in 2-cell embryos before accumulating to approx. 100,000 copies in blastocysts, consistent with degradation of maternal mTEAD mRNAs followed by selective transcription of mTEAD-2 from the zygotic genome. In situ hybridization did not detect mTEAD RNA in oocytes, and only mTEAD-2 was detected in day-7 embryos. Northern analysis detected all three RNAs at varying levels in day-9 embryos and in various adult tissues. A fourth mTEAD gene, recently cloned from a myotube cDNA library, was not detected by RT-PCR in either oocytes or preimplantation embryos. Together, these results reveal that mTEAD-2 is selectively expressed for the first 7 days of embryonic development, and is therefore most likely responsible for the mTEAD transcription factor activity that appears upon zygotic gene activation.

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