A CpG island-encoded mechanism protects genes from premature transcription termination

Abstract

Transcription must be tightly controlled to regulate gene expression and development. However, our understanding of the molecular mechanisms that influence transcription and how these are coordinated in cells to ensure normal gene expression remains rudimentary. Here, by dissecting the function of the SET1 chromatin-modifying complexes that bind to CpG island-associated gene promoters, we discover that they play a specific and essential role in enabling the expression of low to moderately transcribed genes. Counterintuitively, this effect can occur independently of SET1 complex histone-modifying activity and instead relies on an interaction with the RNA Polymerase II-binding protein WDR82. Unexpectedly, we discover that SET1 complexes enable gene expression by antagonising premature transcription termination by the ZC3H4/WDR82 complex at CpG island-associated genes. In contrast, at extragenic sites of transcription, which typically lack CpG islands and SET1 complex occupancy, we show that the activity of ZC3H4/WDR82 is unopposed. Therefore, we reveal a gene regulatory mechanism whereby CpG islands are bound by a protein complex that specifically protects genic transcripts from premature termination, effectively distinguishing genic from extragenic transcription and enabling normal gene expression.

Sequential deregulation of histone marks, chromatin accessibility and gene expression in response to PROTAC-induced degradation of ASH2L

“…Also, thresholds of distinct histone modifications might influence RNAPII loading and activity. Thus, PROTOAC systems as used here and published by others while our work was in progress 55,57,62 , support a determining role of H3K4 methylation in controlling gene transcription and will allow further detailed evaluation to define functions of COMPASS/KMT2 complexes.…”

“…Nevertheless, the role of H3K4me3 is still not fully understood as even small amounts of this histone mark may be sufficient to control RNAPII loading. Unlike loading, COMPASS complexes regulate pausing of RNAPII and premature termination, although the findings are not fully consistent at present 55,57,62 .…”

“…Thus, loss of accessibility is not correlated with a stabilization of a well-positioned mono-nucleosome upstream of TSSs. In this respect it is of note that Set1A and B are located mainly downstream of the TSS 62 . Of note, the pattern of Set1A and B binding closely reflects the distribution of H3K4me3 at promoters, while the ASH2L signals are not biphasic (Fig.…”

“…5). Thus, it appears that KMT2 complexes interact with the nucleosome-free region, possibly by binding to the RNAPII through WDR82 [60][61][62] , or recruitment of KMT2 complexes by other means, including sequence-specific transcription factors, that connect to the RNAPII complex bound at the TSS 27 . This region loses accessibility upon FKBP-HA2-ASH2L loss and nucleosomes are less well-positioned (Fig.…”

Transcriptome-wide analysis of primary human endothelial cell responses to 1 hour of protein translation inhibition identify nonsense mediated decay targets and a non-codingSLC11A2exon as an acute biomarker

“…Further study strengths include identification of processes previously described to be associated with NMD. Identification of the integrator complex is highly relevant to recent data indicating that the integrator complex regulates production of full length coding and non-coding RNAs by mechanisms including RNA cleavage,[53] RNA polymerase II pausing,[54] premature transcriptional termination,[55] and RISC loading of miRNAs. [56] ATP is relevant particularly to UPF1 which has both ATPase and RNA helicase activities.…”