Hit and Run Transcriptional Repressors Are Difficult to Catch in the Act

Abstract

Transcriptional silencing may not necessarily depend on the continuous residence of a sequence‐specific repressor at a control element and may act via a “hit and run” mechanism. Due to limitations in assays that detect transcription factor (TF) binding, such as chromatin immunoprecipitation followed by high‐throughput sequencing (ChIP‐seq), this phenomenon may be challenging to detect and therefore its prevalence may be underappreciated. To explore this possibility, erythroid gene promoters that are regulated directly by GATA1 in an inducible system are analyzed. It is found that many regulated genes are bound immediately after induction of GATA1 but the residency of GATA1 decreases over time, particularly at repressed genes. Furthermore, it is shown that the repressive mark H3K27me3 is seldom associated with bound repressors, whereas, in contrast, the active (H3K4me3) histone mark is overwhelmingly associated with TF binding. It is hypothesized that during cellular differentiation and development, certain genes are silenced by repressive TFs that subsequently vacate the region. Catching such repressor TFs in the act of silencing via assays such as ChIP‐seq is thus a temporally challenging prospect. The use of inducible systems, epitope tags, and alternative techniques may provide opportunities for detecting elusive “hit and run” transcriptional silencing. Also see the video abstract here https://youtu.be/vgrsoP_HF3g.

FBXO11-mediated proteolysis of BAHD1 relieves PRC2-dependent transcriptional repression in erythropoiesis

“…For example, GATA1 facilitates erythropoiesis by activating erythroid genes and repressing those expressed in alternate lineages and HSPCs. [46][47][48][49][50][51][52][53][54] Thus, FBXO11 may repress T-cell and HSPC genes (Figure 3A,C) by facilitating the repressive activities of GATA1. Along the same lines, GATA1 modulates transcription both positively and negatively by displacing GATA2 from many cognate motifs during erythroid maturation, 55,56 and FBXO11 may facilitate this process at some genes.…”

Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes

“…The copyright holder for this preprint (which this version posted April 4, 2023. ; https://doi.org/10.1101/2023.04.02.535219 doi: bioRxiv preprint had been involved in initiation of repression but eventually were packaged into quiescent chromatin, e.g., via a hit-and-run mechanism (Shah et al 2019), would not be detected.…”

“…A fourth limitation is that our inference of repression-related cCREs apply only to those with stable histone modifications. Elements that had been involved in initiation of repression but eventually were packaged into quiescent chromatin, e.g., via a hit-and-run mechanism (Shah et al 2019), would not be detected. A fifth limitation concerns the scale of the studies of epigenetic 29 conservation by correlations of epigenetic states.…”

AR-V7 exhibits non-canonical mechanisms of nuclear import and chromatin engagement in castrate-resistant prostate cancer

“…The high intranuclear mobility of AR-V7 together with its high transcriptional output, suggest a Hit-and-Run model of transcription, where a transcription factor (TF) transiently binds a DNA sequence to regulate target genes (the ‘hit’), and before vacating the site (the ‘run’) recruits secondary TFs which form stable complex at the regulatory site that sustain a stable long-term effect ( Charoensawan et al, 2015 ). Interestingly, the Hit-and-Run is often applied to transcriptional repressors, where gene silencing does not necessarily require continuous TF residence on chromatin ( Shah et al, 2019 ). Importantly, a recent study showed that AR-V7 functions as a transcriptional repressor in CRPC, preferentially binding several co-repressors compared to AR-fl, likely due to differences in H3K27 acetylation ( Cato et al, 2019 ).…”