Lineage specific transcription factors and epigenetic regulators mediate TGFβ-dependent enhancer activation

Abstract

During neurogenesis, dynamic developmental cues, transcription factors and histone modifying enzymes regulate the gene expression programs by modulating the activity of neural-specific enhancers. How transient developmental signals coordinate transcription factor recruitment to enhancers and to which extent chromatin modifiers contribute to enhancer activity is starting to be uncovered. Here, we take advantage of neural stem cells as a model to unravel the mechanisms underlying neural enhancer activation in response to the TGFβ signaling. Genome-wide experiments demonstrate that the proneural factor ASCL1 assists SMAD3 in the binding to a subset of enhancers. Once located at the enhancers, SMAD3 recruits the histone demethylase JMJD3 and the remodeling factor CHD8, creating the appropriate chromatin landscape to allow enhancer transcription and posterior gene activation. Finally, to analyze the phenotypical traits owed to cis-regulatory regions, we use CRISPR–Cas9 technology to demonstrate that the TGFβ-responsive Neurog2 enhancer is essential for proper neuronal polarization.

Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation

“…These data suggest that the observed increase in αKG bioavailability promotes H3K27me2 demethylation at myofibroblast-specific genes in order to promote differentiation. Further evidence in support of our working hypothesis are recent reports suggesting that JMJD3, a JmjC H3K27me2 demethylase with loci specificity, i.e., recruitment to lineage-specific genes, is dependent upon interaction with SMADs 61,62 . Since SMAD2/3 is a canonical transcription factor for TGFβ signaling and myofibroblast activation, it’s intriguing to hypothesize that this interaction may provide myofibroblast-specific demethylation patterns in our model.…”

Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer

“…However, how KDM6A orchestrate p300 and BRD4 recruitment at super-enhancers through shaping chromatin environment and whether its activity requires pre-priming of chromatin accessibility by other pioneer transcription factors need to be further explored. In addition to KDM6A, KDM6B has also been implicated in enhancer regulation in different biological processes 34 , 35 , but whether they act redundantly or non-redundantly in shaping enhancer states remain elusive. Interestingly, current study showed that although KDM6A and KDM6B regulate some target genes in similar manner in HCT116 cells (e.g.…”

PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors

“…Mouse NSCs were prepared from cerebral cortices of C57BL/6J mouse fetal brains (embryonic day [E]12.5). They were cultured in poly-D-lysine (5 μg/mL, 2 h, 37°C) and laminine (5 μg/mL, 4 h, 37°C) precoated dishes (53,54). Cells were maintained in culture as previously described (55) with fibroblast growth factor (FGF) and epidermal growth factor (EGF) to 10 and 20 ng/mL, respectively.…”

“…Embryo developmental stage was determined following HH (59). Embryos were electroporated with the indicated DNAs at 3 μg/μL with 50 ηg/mL of Fast Green as previously described (54,60). Expanded protocol is described in SI Appendix, Materials and Methods.…”

“…ChIP-Seq Procedure. Chromatin immunoprecipitation as well as sample preparation for sequencing from one replicate were done as previously described (54). For details see expanded protocol in SI Appendix, Materials and Methods and Table S2.…”