QSER1 protects DNA methylation valleys from de novo methylation

Science. 2021 Apr 9;372(6538):eabd0875. doi: 10.1126/science.abd0875.

Gary Dixon ^# ¹ ², Heng Pan ^# ³, Dapeng Yang ², Bess P Rosen ¹ ², Therande Jashari ¹ ², Nipun Verma ² ⁴, Julian Pulecio ², Inbal Caspi ¹ ², Kihyun Lee ², Stephanie Stransky ⁵, Abigail Glezer ², Chang Liu ⁶ ⁷, Marco Rivas ⁶ ⁷, Ritu Kumar ⁸, Yahui Lan ⁸, Ingrid Torregroza ⁸, Chuan He ⁶ ⁷, Simone Sidoli ⁵, Todd Evans ⁸, Olivier Elemento ⁹, Danwei Huangfu ¹⁰

Affiliations

1 Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
2 Developmental Biology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
3 Department of Physiology and Biophysics, Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
4 Weill Graduate School of Medical Sciences at Cornell University-The Rockefeller University-Sloan Kettering Institute Tri-Institutional M.D.-Ph.D. Program, New York, NY 10065, USA.
5 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
6 Department of Chemistry, Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
7 Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
8 Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA.
9 Department of Physiology and Biophysics, Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA. [email protected] [email protected].
10 Developmental Biology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA. [email protected] [email protected].
# Contributed equally.

PMID: 33833093 DOI: 10.1126/science.abd0875

Abstract

DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to regulate the methylation landscape remains a central question. Using a knockin DNA methylation reporter, we performed a genome-wide CRISPR-Cas9 screen in human embryonic stem cells to discover DNA methylation regulators. The top screen hit was an uncharacterized gene, QSER1, which proved to be a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA methylation valleys (or canyons). We further demonstrate genetic and biochemical interactions of QSER1 and TET1, supporting their cooperation to safeguard transcriptional and developmental programs from DNMT3-mediated de novo methylation.

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