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Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals

104 Pages Posted: 2 Oct 2019 Sneak Peek Status: Review Complete

See all articles by Jae-Hyun Yang

Jae-Hyun Yang

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Patrick T. Griffin

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Daniel L. Vera

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

John K. Apostolides

Carnegie Mellon University - Computational Biology Department

Motoshi Hayano

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Margarita V. Meer

Harvard Medical School - Genetics Division

Elias L. Salfati

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Qiao Su

Carnegie Mellon University - Computational Biology Department

Elizabeth M. Munding

Dovetail Genomics

Marco Blanchette

Dovetail Genomics

Mital Bhakta

Dovetail Genomics

Zhixun Dou

University of Pennsylvania - Department of Cell and Developmental Biology

Caiyue Xu

University of Pennsylvania - Department of Cell and Developmental Biology

Jeffrey W. Pippin

University of Washington - Division of Nephrology

Michael L. Creswell

University of Washington - Division of Nephrology

Brendan L. O’Connell

University of California, Santa Cruz - Department of Biomolecular Engineering (BME)

Richard E. Green

University of California, Santa Cruz - Department of Biomolecular Engineering (BME)

Benjamin A. Garcia

University of Pennsylvania - Department of Cell and Developmental Biology

Shelley L. Berger

University of Pennsylvania - Department of Cell and Developmental Biology

Philipp Oberdoerffer

National Institutes of Health - Laboratory of Receptor Biology and Gene Expression

Stuart J. Shankland

University of Washington - Division of Nephrology

Vadim N. Gladyshev

Harvard Medical School - Genetics Division

Luis A. Rajman

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Andreas R. Pfenning

Carnegie Mellon University - Computational Biology Department

David A. Sinclair

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

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Abstract

All living things experience entropy, manifested as a loss of inherited genetic and epigenetic information over time. As budding yeast cells age, epigenetic changes result in a loss of cell identity and sterility, both hallmarks of yeast aging. In mammals, epigenetic information is also lost over time, but what causes it to be lost and whether it is a cause or a consequence of aging is not known. Here we show that the transient induction of genomic instability, in the form of a low number of non-mutagenic DNA breaks, accelerates many of the chromatin and tissue changes seen during aging, including the erosion of the epigenetic landscape, a loss of cellular identity, advancement of the DNA methylation clock and cellular senescence. These data support a model in which a loss of epigenetic information is a cause of aging in mammals.

Keywords: DNA damage, chromatin, aging, epigenetic clock, histone modification, RCM(Relocalization of Chromatin Modifiers)

Suggested Citation

Yang, Jae-Hyun and Griffin, Patrick T. and Vera, Daniel L. and Apostolides, John K. and Hayano, Motoshi and Meer, Margarita V. and Salfati, Elias L. and Su, Qiao and Munding, Elizabeth M. and Blanchette, Marco and Bhakta, Mital and Dou, Zhixun and Xu, Caiyue and Pippin, Jeffrey W. and Creswell, Michael L. and O’Connell, Brendan L. and Green, Richard E. and Garcia, Benjamin A. and Berger, Shelley L. and Oberdoerffer, Philipp and Shankland, Stuart J. and Gladyshev, Vadim N. and Rajman, Luis A. and Pfenning, Andreas R. and Sinclair, David A., Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals (September 30, 2019). Available at SSRN: https://ssrn.com/abstract=3461780 or http://dx.doi.org/10.2139/ssrn.3461780
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Jae-Hyun Yang

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

United States

Patrick T. Griffin

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

United States

Daniel L. Vera

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

United States

John K. Apostolides

Carnegie Mellon University - Computational Biology Department

Pittsburgh, PA 15213
United States

Motoshi Hayano

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Margarita V. Meer

Harvard Medical School - Genetics Division ( email )

Boston, MA 02115
United States

Elias L. Salfati

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Qiao Su

Carnegie Mellon University - Computational Biology Department ( email )

Pittsburgh, PA 15213
United States

Elizabeth M. Munding

Dovetail Genomics ( email )

Santa Cruz, CA
United States

Marco Blanchette

Dovetail Genomics ( email )

Santa Cruz, CA
United States

Mital Bhakta

Dovetail Genomics

Santa Cruz, CA
United States

Zhixun Dou

University of Pennsylvania - Department of Cell and Developmental Biology ( email )

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

Caiyue Xu

University of Pennsylvania - Department of Cell and Developmental Biology ( email )

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

Jeffrey W. Pippin

University of Washington - Division of Nephrology ( email )

United States

Michael L. Creswell

University of Washington - Division of Nephrology

United States

Brendan L. O’Connell

University of California, Santa Cruz - Department of Biomolecular Engineering (BME) ( email )

1156 High Street
335 Baskin Engineering Building
Santa Cruz, CA 95064
United States

Richard E. Green

University of California, Santa Cruz - Department of Biomolecular Engineering (BME)

1156 High Street
335 Baskin Engineering Building
Santa Cruz, CA 95064
United States

Benjamin A. Garcia

University of Pennsylvania - Department of Cell and Developmental Biology

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

Shelley L. Berger

University of Pennsylvania - Department of Cell and Developmental Biology ( email )

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

Philipp Oberdoerffer

National Institutes of Health - Laboratory of Receptor Biology and Gene Expression ( email )

Bethesda, MD
United States

Stuart J. Shankland

University of Washington - Division of Nephrology ( email )

United States

Vadim N. Gladyshev

Harvard Medical School - Genetics Division ( email )

Boston, MA 02115
United States

Luis A. Rajman

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Andreas R. Pfenning

Carnegie Mellon University - Computational Biology Department ( email )

Pittsburgh, PA 15213
United States

David A. Sinclair (Contact Author)

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

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