Amazing work by Takeo (@takeo-narita.bsky.social) on these comprehensive analysis and many new insights.

We propose that gene-skipping by enhancers are the exception, not the rule. Linear enhancer-promoter distance and coactivator requirement of genes can predict enhancer targets with accuracy rivalling state-of-the-art experimental approaches.

Multi-way enhancer-promoter interactions in ultra-deep chromatin contact mapping analyses don't indicate co-regulation of multiple promoters. Within multi-way interacting promoters, enhancers regulate proximal promoter but not distal ones.

Attributes of enhancer targets identified by mapping eRNA-PROMPT RNA interactions by RIC-seq are fundamentally different from enhancer targets identified by CRISPRi.

Gene-skipping and non-skipping enhancers differ in chromatin features, target gene distance, activation strength, and coactivator requirements. High H2BNTac strongly predict functional non-skipping enhancers, while skipping enhancers show weaker regulation and higher FDRs.

Gene-skipping enhancer-promoter contacts are rarely confirmed as being functional by CRISPRi screening. Conversely, CRISPRi identified gene-skipping enhancers also seldom show physical interactions.

Mammalian enhancers and GWASs act proximally and seldom skip active genes Enhancers play a critical role in regulating transcription. Nearly 90% of human genetic variants identified in genome-wide association studies (GWAS) are located in distal regions, underscoring the im...

Do enhancers often skip active genes? Our other recent preprint revises current models, that enhancers frequently and by design skip active genes to activate distal targets. Instead simple rules can predict enhancer and GWAS targets. www.biorxiv.org/content/10.1...

Great effort by Takeo and the rest of the team in getting together this work.

Our findings resolve several long-standing conundrums regarding the involvement of cohesin and CTCF in gene regulation, and we present a unified model for their combined and individual roles acting directly near promoters or in concert with p300/CBP-dependent enhancers.

For the genes regulated by CTCF at the promoter, CTCF directly impacts DNA accessibility and downstream recruitment of PolII.

The CTCF-like protein BORIS is also unable to anchor cohesin. Re-analysis of published data with this new perspective show, that unlike CTCF, BORIS has no impact on enhancer-regulated genes. In contrast, BORIS can selectively rescue expression of promoter-activated genes.

Using a cohesin-loop-deficient CTCF mutant, we reveal that CTCF is a position- and orientation-dependent transcription activator at promoters. It directly activates hundreds of essential housekeeping genes—independently of cohesin and enhancers—even in plasmid reporter assays.

Among diverse types of posited enhancers, cohesin seems to uniquely facilitate enhancer-mediated gene regulation through p300/CBP-dependent enhancers.

Acute depletion of cohesin and CTCF dysregulate several hundreds of genes – far more than previously appreciated. Many of these are subtle, but as confirmed through several repetitions, they are consistent.

A unified model of gene expression control by cohesin and CTCF Cohesin and CTCF fold vertebrate genomes into loops and topologically associating domains (TADs). The genome folding by cohesin and CTCF is considered crucial for enhancer-promoter communication and g...

How do cohesin and CTCF control gene expression and what are their links to enhancers? Our new preprint unravels their shared and unique roles: from precise enhancer targeting to direct transcriptional activator functions of CTCF!
#Genomics #CTCF #Cohesin
www.biorxiv.org/content/10.1...