Formation of Chromosomal Domains by Loop Extrusion

Cohesin Loss Eliminates All Loop Domains

Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization.

Multiscale 3D Genome Rewiring during Mouse Neural Development

CCCTC-binding factor (CTCF) is a DNA-binding protein that has various, often seemingly contradictory, roles in gene regulation. This Review describes these disparate functions and how the context-dependent looping of DNA regions by CTCF is emerging as a potential unifying mechanism that underpins these diverse roles.

CTCF: an architectural protein bridging genome topology and function

CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function

The closely linked human protocadherin (Pcdh) α, β, and γ gene clusters encode 53 distinct protein isoforms, which are expressed in a combinatorial manner to generate enormous diversity on the surface of individual neurons. This diversity is a consequence of stochastic promoter choice and alternative pre-mRNA processing. Here, we show that Pcdhα promoter choice is achieved by DNA looping between two downstream transcriptional enhancers and individual promoters driving the expression of alternate Pcdhα isoforms. In addition, we show that this DNA looping requires specific binding of the CTCF/cohesin complex to two symmetrically aligned binding sites in both the transcriptionally active promoters and in one of the enhancers. These findings have important implications regarding enhancer/promoter interactions in the generation of complex Pcdh cell surface codes for the establishment of neuronal identity and self-avoidance in individual neurons.

https://www.pnas.org/content/pnas/109/51/21081.full.pdf

CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)—a prominent neurotransmitter—in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression. 

Haiyang Wu

Papers

CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function

CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression