Synapse - Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions

Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions Journal Article

Authors:	Luo, R.; Yan, J.; Oh, J. W.; Xi, W.; Shigaki, D.; Wong, W.; Cho, H. S.; Murphy, D.; Cutler, R.; Rosen, B. P.; Pulecio, J.; Yang, D.; Glenn, R. A.; Chen, T.; Li, Q. V.; Vierbuchen, T.; Sidoli, S.; Apostolou, E.; Huangfu, D.; Beer, M. A.
Article Title:	Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions
Abstract:	Comprehensive enhancer discovery is challenging because most enhancers, especially those contributing to complex diseases, have weak effects on gene expression. Our gene regulatory network modeling identified that nonlinear enhancer gene regulation during cell state transitions can be leveraged to improve the sensitivity of enhancer discovery. Using human embryonic stem cell definitive endoderm differentiation as a dynamic transition system, we conducted a mid-transition CRISPRi-based enhancer screen. We discovered a comprehensive set of enhancers for each of the core endoderm-specifying transcription factors. Many enhancers had strong effects mid-transition but weak effects post-transition, consistent with the nonlinear temporal responses to enhancer perturbation predicted by the modeling. Integrating three-dimensional genomic information, we were able to develop a CTCF-loop-constrained Interaction Activity model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer–promoter contact frequency. Our study provides generalizable strategies for sensitive and systematic enhancer discovery in both normal and pathological cell state transitions. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords:	genetics; transcription factor; cell differentiation; transcription factors; gene expression regulation; chromatin; gene regulatory network; enhancer region; enhancer elements, genetic; gene regulatory networks; humans; human
Journal Title:	Nature Genetics
Volume:	55
Issue:	8
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Date Published:	2023-08-01
Start Page:	1336
End Page:	1346
Language:	English
DOI:	10.1038/s41588-023-01450-7
PUBMED:	37488417
PROVIDER:	scopus
PMCID:	PMC11012226
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85165594415&doi=10.1038%2fs41588-023-01450-7&partnerID=40&md5=ea05c6042149b60133e2e573d18f0294
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Danwei Huangfu -- Source: Scopus