RNA-binding proteins mediate the maturation of chromatin topology during differentiation
Topologically associating domains (TADs) and chromatin architectural loops impact promoter-enhancer interactions, with CCCTC-binding factor (CTCF) defining TAD borders and loop anchors. TAD boundaries and loops progressively strengthen upon embryonic stem (ES) cell differentiation, underscoring the importance of chromatin topology in ontogeny. However, the mechanisms driving this process remain unclear. Here we show a widespread increase in CTCF-RNA-binding protein (RBP) interactions upon ES to neural stem (NS) cell differentiation. While dispensable in ES cells, RBPs reinforce CTCF-anchored chromatin topology in NS cells. We identify Pantr1, a non-coding RNA, as a key facilitator of CTCF-RBP interactions, promoting chromatin maturation. Using acute CTCF degradation, we find that, through its insulator function, CTCF helps maintain neuronal gene silencing in NS cells by acting as a barrier to untimely gene activation during development. Altogether, we reveal a fundamental mechanism driving developmentally linked chromatin structural consolidation and the contribution of this process to the control of gene expression in differentiation.
Authors
- Mahmoud‐Reza Rafiee (ORCID: https://orcid.org/0000-0002-1317-1162)
- Aleksandra Piotrowska (ORCID: https://orcid.org/0000-0003-4093-7386)
- Debasish Chaudhury (ORCID: https://orcid.org/0000-0002-9089-732X)
- Jacqueline Severino (ORCID: https://orcid.org/0000-0001-6959-0342)
- Marcin Janowski (ORCID: https://orcid.org/0000-0002-9626-3467)
- Rafael Casellas (ORCID: https://orcid.org/0000-0001-9282-2287)
- Paweł Dłotko (ORCID: https://orcid.org/0000-0001-5352-3102)
- Payman Zare (ORCID: https://orcid.org/0000-0003-1291-1808)
- Wolfgang K. Huber (ORCID: https://orcid.org/0000-0002-0474-2218)
- Timo Zimmermann (ORCID: https://orcid.org/0000-0001-7098-0700)
- Sharif Iqbal (ORCID: https://orcid.org/0000-0002-0366-2080)
- Rogelio Montiel-Manríquez (ORCID: https://orcid.org/0000-0001-8051-229X)
- Aleksandra Pękowska (ORCID: https://orcid.org/0000-0002-0425-4388)
- Misbah Abbas (ORCID: https://orcid.org/0000-0002-0100-7488)
- Bondita Dehingia (ORCID: https://orcid.org/0000-0003-3688-4680)
- Jan F. Senge (ORCID: https://orcid.org/0000-0002-2889-5489)
- Dietrich W. M. Walsh (ORCID: https://orcid.org/0000-0003-2067-1883)
- Jeroen Krijgsveld (ORCID: https://orcid.org/0000-0001-7549-9326)
- Jianliang Xu (ORCID: https://orcid.org/0000-0003-4154-4322)
- Sylwia Jankowska
- Małgorzata Milewska-Puchała
- Piotr Blaut
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
- German Cancer Research Center (DE)
- Georgia State University (US)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Centre for Genomic Regulation (ES)
- European Molecular Biology Laboratory (DE)
- Instituto Nacional de Cancerología (MX)
- Universidad Nacional Autónoma de México (MX)
- Polish Academy of Sciences (PL)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s41556-025-01735-5
- Citations
- 4
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 3.22