7SK-BAF axis controls pervasive transcription at enhancers

Abstract

RNA functions at enhancers remain mysterious. Here we show that the 7SK small nuclear RNA (snRNA) inhibits enhancer transcription by modulating nucleosome position. 7SK occupies enhancers and super enhancers genome-wide in mouse and human cells, and 7SK is required to limit eRNA initiation and synthesis in a manner distinct from promoter pausing. Clustered elements at super enhancers uniquely require 7SK to prevent convergent transcription and DNA damage signaling. 7SK physically interacts with the BAF chromatin remodeling complex, recruit BAF to enhancers, and inhibits enhancer transcription by modulating chromatin structure. In turn, 7SK occupancy at enhancers coincides with Brd4 and is exquisitely sensitive to the bromodomain inhibitor JQ1. Thus, 7SK employs distinct mechanisms to counteract diverse consequences of pervasive transcription that distinguish super enhancers, enhancers, and promoters.

ATP-dependent chromatin remodeling during mammalian development

“…BAF complex-mediated chromatin reorganization by virtue of nucleosome redistribution appears to play a central role in regulating the transcriptional outcomes in different tissue types, with tissue specificity attributed to temporal expression and association of specific subunits with specialized BAF complexes. Furthermore, BAF complexes also function via non-coding RNAs (Flynn et al, 2016;Han et al, 2014;Prensner et al, 2013) and might mediate long-range chromosomal interactions to regulate gene expression. As new subunits are identified (for example the B-cell lymphoma family of proteins, such as BCL7A-C, BCL11A,B and bromodomain-containing proteins BRD7,9) and found to be part of stable BAF complexes Kaeser et al, 2008), analyzing the function of these subunits in in vitro biochemical assays and via in vivo genetic perturbations may provide new insights into the role of these specialized BAF complexes.…”

Transcription elongation control by the 7SK snRNP complex: Releasing the pause

“…35 This study found higher levels of 7SK RNA occupancy at traditional and super enhancers compared to promoters, and that deposition of the non-coding RNA at enhancers directly influenced transcriptional activity (enhancer RNA synthesis). Interestingly, the disproportionately high levels of 7SK RNA found at enhancers in mouse embryonic stem cells were not to be mirrored by levels of the Hexim protein.…”

“…27,28 While P-TEFb has been proposed to be inducibly recruited to gene promoters during transcriptional activation, 10,[20][21][22][23]26,29 several recent reports have shown that inactive P-TEFb (as part of the 7SK snRNP complex) is localized to promoter-proximal regions and enhancers genome-wide prior to, or during, gene activation. 24,[30][31][32][33][34][35][36][37] Recruitment of catalytically inactive P-TEFb to gene promoters and enhancers has shifted our understanding on how the cell controls transcription elongation. By localizing primed P-TEFb near paused Pol II, transcription factors can promote kinase activation to facilitate pause release (Fig.…”

“…Taken together, while P-TEFb release from the 7SK snRNP can be accomplished through the activity of various enzymes/ factors, all of these observations point toward a unifying model of 7SK snRNP disassembly and P-TEFb release/activation on chromatin, where transcription and pre-mRNA processes occur. 24,[31][32][33][35][36][37]88 Therefore, activation of P-TEFb can occur 'on-site', in direct proximity to the paused Pol II complex.…”

An evolutionary conserved Hexim1 peptide binds to the Cdk9 catalytic site to inhibit P-TEFb

“…As a consequence, the overall P-TEFb activity increases on inhibition of transcription (3,4). Thus, in addition to other more specific functions (13)(14)(15), 7SK RNA serves as a sensor of transcriptional activity through a feedback loop, fine-tuning P-TEFb activity (10). Understanding how this noncoding RNA mechanistically regulates the activity of P-TEFb, a central transcription factor, remains challenging.…”