# A novel functional interaction between a chromatin remodeler and cohesin in neuronal activity-induced enhancer architecture

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $451,000

## Abstract

Summary:
Genome architecture, especially cohesin-mediated enhancer-promoter (E-P) looping, is a critical step for
enhancer activation and gene transcription. It remains largely unknown how chromatin regulators, which often
function locally at enhancers and promoters, affect long range E-P looping. BAF chromatin remodeling
complexes regulate transcription using energy derived from ATP hydrolysis to modulate chromatin accessibilities
and the local chromatin environment. Cohesin complexes form a ring-like structure to mediate chromosome
organization, including E-P looping, during the G0/G1 phase. Genetic mutations in both BAF and cohesin
subunits are associated with neural developmental disorders, which
share similarities in symptoms.
Activity-
regulated gene (ARG) expression plays an essential role in short-term neural responses as well as in long-term
memory formation, homeostasis, and adaptation. In response to neuronal activation, cohesin-mediated E-P
interactions either form de novo or become strengthened, a critical step in enhancer activation and ARG
expression. However, it remains unclear how neuronal activities promote cohesin function in enhancer activation.
Recently, we reported that BRG1, a core ATPase subunit in BAF complexes, plays a central role in regulating
enhancer activities, and we identified a phosphorylation event that fine-tunes BRG1 function in response to
neuronal stimulation. We showed that BRG1 deletion as well as BRG1 phospho-mutations led to impaired
enhancer activation and E-P looping in response to neuronal activities. It remains unclear how locally functioning
chromatin remodelers regulate cohesin binding and long-range E-P looping. A recently revealed important
mechanism regulating cohesin binding to enhancers is the binding mobility of cohesin to chromatin. The cohesin
release factor WAPL maintains a pool of dynamic cohesin, which is required for cohesin binding to enhancers
and the expression of lineage-specific genes. We performed preliminary studies in HeLa cells and in primary
neurons and observed that BRG1 had a similar function in regulating cohesin dynamics and in regulating the
global distribution of cohesin on chromatin. BRG1 deletion led to a global increase in cohesin binding to
chromatin but a paradoxical decrease in its binding to specific enhancers and promoters. BRG1 enhanced WAPL
function in cohesin release, and BRG1 deletion impaired cohesin dynamics. Since the BAF complex can use the
energy derived from ATP hydrolysis to improve the mobility of not only DNA bound histones, but also other
proteins including itself and the PRC1 complex, it could also mobilize chromatin-bound cohesin. We hypothesize
that BRG1 and its phosphorylation could promote neuronal activity-induced cohesin dynamics, cohesin global
redistribution on chromatin, and cohesin-mediated E-P looping. Using BRG1 and cohesin mutant mice and novel
genome-wide techniques, we will study how BRG1 regulates cohesin chromatin distribution and ...

## Key facts

- **NIH application ID:** 10537687
- **Project number:** 1R21NS127401-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jiang Wu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $451,000
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537687

## Citation

> US National Institutes of Health, RePORTER application 10537687, A novel functional interaction between a chromatin remodeler and cohesin in neuronal activity-induced enhancer architecture (1R21NS127401-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10537687. Licensed CC0.

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