Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome

Heintzman, Nathaniel D.; Stuart, Rhona; Hon, Gary C.; Fu, Yutao; Ching, Christina W.; Hawkins, R. David; Barrera, Leah O.; Calcar, Sara Van; Qu, Chunxu; Ching, Keith A.; Wang, Wei; Weng, Zhiping; Green, Roland D.; Crawford, Gregory E.; Ren, Bing

doi:10.1038/ng1966

Cited by 2,990 publications

(3,087 citation statements)

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“…H3K4me1 also broadly marks distal regulatory regions. In contrast, H3K27me3 has been proposed to accumulate on silent but poised enhancers and promoters of repressed genes (Heintzman et al , 2007, 2009; Rada‐Iglesias et al , 2011). Therefore, enrichment for H3K4me1, H3K4me3, H3K27ac, and H3K27me3 at the Esrrb and Nanog enhancers/promoters was determined in the three ESC populations.…”

Section: Resultsmentioning

confidence: 99%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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Self‐renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESCs with distinct TF expression levels from LIF/FCS cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanoglow cells. Independent Esrrb reporter lines demonstrate that Esrrbnegative ESCs cannot effectively self‐renew. Upon Esrrb loss, pre‐implantation pluripotency gene expression collapses. ChIP‐Seq identifies different regulatory element classes that bind both OCT4 and NANOG in Esrrbpositive cells. Class I elements lose NANOG and OCT4 binding in Esrrbnegative ESCs and associate with genes expressed preferentially in naïve ESCs. In contrast, Class II elements retain OCT4 but not NANOG binding in ESRRB‐negative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency.

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Section: Resultsmentioning

confidence: 99%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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“…In addition, overexpression of p300 has been correlated to an increased H3K9 acetylation at distinct loci in primary hepatocytes [25]. Therefore, p300 occupancy is known as the best chromatin signature of enhancers and has emerged as a valuable perception to identify novel regulatory elements for studies of transcriptional control, in addition to DNA sequence motifs [2,26–32]. …”

Section: Introductionmentioning

confidence: 99%

Loci-specific histone acetylation profiles associated with transcriptional coactivator p300 during early myoblast differentiation

et al. 2018

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Molecular regulation of stem cell differentiation is exerted through both genetic and epigenetic determinants over distal regulatory or enhancer regions. Understanding the mechanistic action of active or poised enhancers is therefore imperative for control of stem cell differentiation. Based on the genome-wide co-occurrence of different epigenetic marks in committed proliferating myoblasts, we have previously generated a 14-state chromatin state model to profile rexinoid-responsive histone acetylation in early myoblast differentiation. Here, we delineate the functional mode of transcription regulators during early myogenic differentiation using genome-wide chromatin state association. We define a role of transcriptional coactivator p300, when recruited by muscle master regulator MyoD, in the establishment and regulation of myogenic loci at the onset of myoblast differentiation. In addition, we reveal an enrichment of loci-specific histone acetylation at p300 associated active or poised enhancers, particularly when enlisted by MyoD. We provide novel molecular insights into the regulation of myogenic enhancers by p300 in concert with MyoD. Our studies present a valuable aptitude for driving condition-specific chromatin state or enhancers pharmacologically to treat muscle-related diseases and for the identification of additional myogenic targets and molecular interactions for therapeutic development.Abbreviations: MRF: Muscle regulatory factor; HAT: Histone acetyltransferase; CBP: CREB-binding protein; ES: Embryonic stem; ATCC: American type culture collection; DM: Differentiation medium; DMEM: Dulbecco’s Modified Eagle Medium; GM: Growth medium; GO: Gene ontology; GREAT: Genomic regions enrichment of annotations tool; FPKM: Fragments per kilobase of transcript per million; GEO: Gene expression omnibus; MACS: Model-based analysis for ChIP-seq

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“…We did not observe an effect of nutrient-deprivation on global expression of these histone marks (Figure S4). Next, to evaluate whether nutrient deprivation may result in a more specific redistribution of chromatin marks, ChIP-sequencing was performed for histone marks associated with active transcription (H3K4me3 [24], H3K27ac [25], and H3K56ac [26]). Short-term nutrient deprivation resulted in alterations in all 3 histone marks (Figure 4(a)).…”

Section: Resultsmentioning

confidence: 99%

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

et al. 2018

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Macroautophagy (hereafter autophagy) is a lysosomal degradation pathway critical for maintaining cellular homeostasis and viability, and is predominantly regarded as a rapid and dynamic cytoplasmic process. To increase our understanding of the transcriptional and epigenetic events associated with autophagy, we performed extensive genome-wide transcriptomic and epigenomic profiling after nutrient deprivation in human autophagy-proficient and autophagy-deficient cells. We observed that nutrient deprivation leads to the transcriptional induction of numerous autophagy-associated genes. These transcriptional changes are reflected at the epigenetic level (H3K4me3, H3K27ac, and H3K56ac) and are independent of autophagic flux. As a proof of principle that this resource can be used to identify novel autophagy regulators, we followed up on one identified target: EGR1 (early growth response 1), which indeed appears to be a central transcriptional regulator of autophagy by affecting autophagy-associated gene expression and autophagic flux. Taken together, these data stress the relevance of transcriptional and epigenetic regulation of autophagy and can be used as a resource to identify (novel) factors involved in autophagy regulation.

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Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome

Cited by 2,990 publications

References 34 publications

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Loci-specific histone acetylation profiles associated with transcriptional coactivator p300 during early myoblast differentiation

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

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