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CRISPR-Mediated Reorganization of Chromatin Loop Structure
Published on: September 14, 2018
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Phase separation drives aberrant chromatin looping and cancer development
Jeong Hyun Ahn1,2, Eric S Davis3, Timothy A Daugird4
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Nature
|June 24, 2021
Summary
Intrinsically disordered regions (IDRs) in cancer proteins drive oncogenesis by forming phase-separated condensates. These condensates enhance gene targeting and alter 3D chromatin structure, promoting leukemia development.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Cancer development is linked to genetic changes affecting proteins with intrinsically disordered regions (IDRs).
- Nucleoporin chimeras, such as NUP98-HOXA9 found in leukemia, contain these IDRs, but their role in oncogenesis is unknown.
Purpose of the Study:
- To investigate the role of intrinsically disordered regions (IDRs) in NUP98-HOXA9 in leukaemic transformation.
- To understand how these IDRs influence transcription factor behavior and chromatin organization.
Main Methods:
- Studied the function of IDRs in NUP98-HOXA9 in liquid-liquid phase separation (LLPS) and leukaemic transformation.
- Utilized an artificial HOX chimera with an unrelated IDR to assess LLPS-driven effects.
- Employed deep-sequenced Hi-C to analyze genome-wide chromatin interactions.
Main Results:
- IDRs in NUP98-HOXA9 are essential for forming phase-separated condensates and inducing leukemia.
- LLPS of NUP98-HOXA9 enhances its chromatin occupancy and creates super-enhancer-like patterns at leukaemogenic genes.
- Phase-separated NUP98-HOXA9 induces CTCF-independent chromatin loops at proto-oncogenes.
Conclusions:
- Cancer can utilize mutations to create oncogenic transcription factor condensates via LLPS, enhancing gene targeting and altering 3D chromatin structure.
- This mechanism of phase separation driving oncogenesis may be broadly applicable to various diseases involving LLPS-competent molecules.
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