Expression Noise and Acetylation Profiles Distinguish HDAC Functions

Weinberger, Leehee; Voichek, Yoav; Tirosh, Itay; Hornung, Gil; Amit, Ido; Barkai, Naama

doi:10.1016/j.molcel.2012.05.008

Cited by 120 publications

(131 citation statements)

References 56 publications

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“…Consistent with SETD5 being recruited with PAF1C and NCoR to actively transcribed genes, Setd5 null mESCs have slightly increased H3K36 methylation, a cotranscriptional histone modification that is enriched over the coding region of genes. Moreover, we did not observe any global changes in H3K4 methylation, which is typically associated with active promoter regions, suggesting that SETD5/HDAC3 repression might mostly target transcriptional elongation, as does the yeast SET3C complex (Weinberger et al, 2012). In mammals, several HATs and HDACs have been shown to be targeted to the transcribed regions of active genes by phosphorylated RNAP II (Wang et al, 2009).…”

Section: Lhx1mentioning

confidence: 69%

Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation

et al. 2016

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SET domain-containing proteins play a vital role in regulating gene expression during development through modifications in chromatin structure. Here we show that SET domain-containing 5 (Setd5) is divergently transcribed with Gt(ROSA26)Sor, is necessary for mammalian development, and interacts with the PAF1 co-transcriptional complex and other proteins. Setd5-deficient mouse embryos exhibit severe defects in neural tube formation, somitogenesis and cardiac development, have aberrant vasculogenesis in embryos, yolk sacs and placentas, and die between embryonic day 10.5 and 11.5. Setd5-deficient embryonic stem cells have impaired cellular proliferation, increased apoptosis, defective cell cycle progression, a diminished ability to differentiate into cardiomyocytes and greatly perturbed gene expression. SETD5 co-immunoprecipitates with multiple components of the PAF1 and histone deacetylase-containing NCoR complexes and is not solely required for major histone lysine methylation marks. In the absence of Setd5, histone acetylation is increased at transcription start sites and near downstream regions. These findings suggest that SETD5 functions in a manner similar to yeast Set3p and Drosophila UpSET, and that it is essential for regulating histone acetylation during gene transcription.

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Section: Lhx1mentioning

confidence: 69%

Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation

et al. 2016

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“…Eviction of acetylated nucleosomes ahead of Pol II permits efficient elongation, whereas reassembly of deacetylated nucleosomes behind the elongating polymerase prevents initiation at spurious sites. Consistent with this scenario, mutations in histone chaperones that promote nucleosome assembly/disassembly, or in enzyme complexes that catalyze or erase histone modifications associated with gene bodies (e.g., H3K9/14 and H4 acetylation, H2B ubiquitylation, and H3K36 di-and trimethylation), affect transcriptional consistency in yeast (49,(53)(54)(55).…”

Section: Discussionmentioning

confidence: 88%

“…Variations in gene expression patterns within a single cell can be assessed by comparing the levels of two different reporter genes driven off the same promoter (intrinsic noise), whereas those that occur between cells (extrinsic noise) can be examined in many ways, including single-cell RNA sequencing, the technique we have used here (44)(45)(46). Cell-to-cell variability in gene expression reflects stochastic variation, differences in cell state or environmental input, and gene regulatory processes including the frequency and robustness of transcriptional initiation (46), the relative abundance of transcriptional regulators (47,48), the size and frequency of transcriptional bursts (49), the spatial organization of the genome (50), and the relative efficiency of transcription vs. translation (51) (reviewed in refs. 45,52).…”

Section: Discussionmentioning

confidence: 99%

“…In mammalian cells, TET functions are linked to both types of histone modifications: high levels of 5hmC are present in the gene bodies of expressed genes; 5hmC distribution in gene bodies is strongly correlated with that of H3K36me3 (43,(56)(57)(58)(59)(60); and TET1 coimmunoprecipitates with SIN3A and HDAC1/2 in mouse ES cells (61). (ii) Also in yeast, H2B ubiquitylation has been implicated in nucleosome dynamics (54,55), and a screen for chromatin regulators that altered the variability of reporter expression in yeast showed that H2B ubiquitylation recruited the Set3C HDAC complex, thereby limiting the high rate of Pol II elongation associated with transcriptional bursts (49). Similarly in mammalian cells, TET2 and TET3 have been linked to H2B ubiquitination through their association with the enzyme O-GlcNAc transferase (OGT) (62-64); OGT attaches O-linked N-acetylglucosamine to H2B (63), a modification required for subsequent H2B ubiquitylation (65).…”

Section: Discussionmentioning

confidence: 99%

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Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis

Kang

Lienhard

Pastor

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

101

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Dioxygenases of the TET (Ten-Eleven Translocation) family produce oxidized methylcytosines, intermediates in DNA demethylation, as well as new epigenetic marks. Here we show data suggesting that TET proteins maintain the consistency of gene transcription. Embryos lacking Tet1 and Tet3 (Tet1/3 DKO) displayed a strong loss of 5-hydroxymethylcytosine (5hmC) and a concurrent increase in 5-methylcytosine (5mC) at the eight-cell stage. Single cells from eight-cell embryos and individual embryonic day 3.5 blastocysts showed unexpectedly variable gene expression compared with controls, and this variability correlated in blastocysts with variably increased 5mC/5hmC in gene bodies and repetitive elements. Despite the variability, genes encoding regulators of cholesterol biosynthesis were reproducibly down-regulated in Tet1/3 DKO blastocysts, resulting in a characteristic phenotype of holoprosencephaly in the few embryos that survived to later stages. Thus, TET enzymes and DNA cytosine modifications could directly or indirectly modulate transcriptional noise, resulting in the selective susceptibility of certain intracellular pathways to regulation by TET proteins.DNA methylation | cholesterol biosynthesis | TET methylcytosine oxidases | 5-hydroxymethylcytosine | 5hmC

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“…This might occur by influencing the frequency of transcription initiation (defined as loading of the RNA polymerase), by transition to the elongating form or by impeding the rate of the transcribing RNA polymerase. Evidence for co-repressor proteins exerting exactly this kind of fine transcriptional control came initially from yeast, in which chromatin-modifying proteins were shown to influence transcriptional 'noise' (Huang, 2009) and absolute levels of transcription (Raser and O'Shea, 2004;Weinberger et al, 2012). More recently, it was shown that the lysine deacetylase-containing NuRD complex can influence both of these distinct aspects of transcriptional output in mammalian cells, and that this level of transcriptional control is essential to maintain the developmental responsiveness of pluripotent cells (Reynolds et al, 2012a).…”

Section: Repressors As Fine-tuners Of Gene Expression and Cell Fatementioning

confidence: 99%

Transcriptional repressors: multifaceted regulators of gene expression

2013

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SummaryThrough decades of research it has been established that some chromatin-modifying proteins can repress transcription, and thus are generally termed 'repressors'. Although classic repressors undoubtedly silence transcription, genome-wide studies have shown that many repressors are associated with actively transcribed loci and that this is a widespread phenomenon. Here, we review the evidence for the presence of repressors at actively transcribed regions and assess what roles they might be playing. We propose that the modulation of expression levels by chromatin-modifying, co-repressor complexes provides transcriptional fine-tuning that drives development.Key words: NuRD, Chromatin, co-repressor, Deacetylase, Histone, Transcription IntroductionEvery major developmental process may be regarded as being driven by changes in gene expression patterns. It is crucial that such changes, either throughout development or in response to environmental stimuli, are tightly regulated. For any given cell type, distinct transcriptional programmes must be established whereby certain genes are transcribed and others remain silent. At the same time, cells must remain responsive to changes in their environment or to developmental signals, for which the ability to rapidly change transcription patterns is essential.The control of gene expression programmes is inextricably linked to the local state of chromatin, the form in which DNA is packaged within the cell. DNA in eukaryotic nuclei is packaged with histone proteins into nucleosomes (Kornberg, 1974). Posttranslational modification of histone tails within the nucleosome may occur through the addition of a multitude of different chemical modifications, including acetylation, methylation and phosphorylation, at specific sites. These modifications influence gene expression patterns either by altering chromatin conformation, and thereby allowing or restricting access of transcription factors to that locus, or by changing interactions of transcription factors with the nucleosomes themselves (Berger, 2007; Kouzarides, 2007).It is generally accepted that chromatin state correlates with transcriptional state; histone acetylation, for example, has most often been associated with active transcription whereas deacetylation is associated with silencing (Bannister and Kouzarides, 1996;Strahl and Allis, 2000). It therefore follows that lysine acetyltransferases (KATs), which catalyse acetylation of lysine residues, act as transcriptional activators, and lysine deacetylases (KDACs), which remove acetyl groups from acetylated lysines, act as repressors. This correlation is supported by experiments in which chromatin modifiers were found to activate or repress transcription, often in reporter gene assays (Grunstein, 1997;Pazin and Kadonaga, 1997;Wolffe, 1997;Yang and Seto, 2007). Although such a binary model of transcription factor-mediated gene expression was very important in the early stages of understanding how these proteins work at a general level, it has proven to be too simplistic to ...

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Expression Noise and Acetylation Profiles Distinguish HDAC Functions

Cited by 120 publications

References 56 publications

Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation

Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation

Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis

Transcriptional repressors: multifaceted regulators of gene expression

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