QSER1 protects DNA methylation valleys from de novo methylation

Gary Dixon; Heng Pan; Dapeng Yang; Bess P. Rosen; Therande Jashari; Nipun Verma; Julian Pulecio; Inbal Caspi; Kihyun Lee; Stephanie Stransky; Abigail Glezer; Chang Liu; Marco Rivas; Ritu Kumar; Yahui Lan; Ingrid Torregroza; Chuan He; Simone Sidoli; Todd Evans; Olivier Elemento; Danwei Huangfu

doi:10.1126/science.abd0875

QSER1 protects DNA methylation valleys from de novo methylation

Gary Dixon, Heng Pan, Dapeng Yang, Bess P. Rosen, Therande Jashari, Nipun Verma, Julian Pulecio, Inbal Caspi, Kihyun Lee, Stephanie Stransky, Abigail Glezer, Chang Liu, Marco Rivas, Ritu Kumar, Yahui Lan, Ingrid Torregroza, Chuan He, Simone Sidoli, Todd Evans, Olivier ElementoDanwei Huangfu

Biochemistry

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

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.

Original language	English (US)
Article number	eabd0875
Journal	Science
Volume	372
Issue number	6538
DOIs	https://doi.org/10.1126/science.abd0875
State	Published - Apr 9 2021

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Dixon, G., Pan, H., Yang, D., Rosen, B. P., Jashari, T., Verma, N., Pulecio, J., Caspi, I., Lee, K., Stransky, S., Glezer, A., Liu, C., Rivas, M., Kumar, R., Lan, Y., Torregroza, I., He, C., Sidoli, S., Evans, T., ... Huangfu, D. (2021). QSER1 protects DNA methylation valleys from de novo methylation. Science, 372(6538), Article eabd0875. https://doi.org/10.1126/science.abd0875

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title = "QSER1 protects DNA methylation valleys from de novo methylation",

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.",

author = "Gary Dixon and Heng Pan and Dapeng Yang and Rosen, {Bess P.} and Therande Jashari and Nipun Verma and Julian Pulecio and Inbal Caspi and Kihyun Lee and Stephanie Stransky and Abigail Glezer and Chang Liu and Marco Rivas and Ritu Kumar and Yahui Lan and Ingrid Torregroza and Chuan He and Simone Sidoli and Todd Evans and Olivier Elemento and Danwei Huangfu",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

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doi = "10.1126/science.abd0875",

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AU - Dixon, Gary

AU - Pan, Heng

AU - Yang, Dapeng

AU - Rosen, Bess P.

AU - Jashari, Therande

AU - Verma, Nipun

AU - Pulecio, Julian

AU - Caspi, Inbal

AU - Lee, Kihyun

AU - Stransky, Stephanie

AU - Glezer, Abigail

AU - Liu, Chang

AU - Rivas, Marco

AU - Kumar, Ritu

AU - Lan, Yahui

AU - Torregroza, Ingrid

AU - He, Chuan

AU - Sidoli, Simone

AU - Evans, Todd

AU - Elemento, Olivier

AU - Huangfu, Danwei

PY - 2021/4/9

Y1 - 2021/4/9

N2 - 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.

AB - 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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QSER1 protects DNA methylation valleys from de novo methylation

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