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Genome-wide DNA methylation and multi-omics study of human chondrocyte ontogeny and an epigenetic clock analysis of adult chondrocytes

Arijita Sarkar, Siyoung Lee, Ruzanna Shkhyan, Nancy Q. Liu, Ben Van Handel, Jenny Magallanes, Youngjoo Lee, Litao Tao, Neil Segil, Jason Ernst, Steve Horvath, Denis Evseenko
doi: https://doi.org/10.1101/2021.08.02.454544
Arijita Sarkar
1Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, 90033, USA
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Siyoung Lee
1Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, 90033, USA
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Ruzanna Shkhyan
1Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, 90033, USA
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Nancy Q. Liu
1Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, 90033, USA
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Ben Van Handel
1Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, 90033, USA
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Jenny Magallanes
1Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, 90033, USA
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Youngjoo Lee
1Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, 90033, USA
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Litao Tao
2Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, CA, 90033, USA
3Eli and Edythe Broad Center, University of Southern California, Los Angeles, CA, 90033, USA
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Neil Segil
2Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, CA, 90033, USA
3Eli and Edythe Broad Center, University of Southern California, Los Angeles, CA, 90033, USA
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Jason Ernst
4Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA
5Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, Los Angeles, CA 90095, USA
6Computer Science Department, University of California, Los Angeles, CA 90095, USA
7Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA
8Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA
9Department of Computational Medicine, University of California, Los Angeles, CA 90095, USA
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Steve Horvath
10Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA 90095, USA
11Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
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  • For correspondence: evseenko@usc.edu
Denis Evseenko
1Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, 90033, USA
2Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, CA, 90033, USA
3Eli and Edythe Broad Center, University of Southern California, Los Angeles, CA, 90033, USA
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  • For correspondence: evseenko@usc.edu
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Abstract

Articular chondrocytes undergo functional changes and their regenerative potential declines with age. Although the molecular mechanisms guiding articular cartilage aging is poorly understood, DNA methylation is known to play a mechanistic role in aging. However, our understanding of DNA methylation in chondrocyte development across human ontogeny is limited. To better understand DNA methylome changes, methylation profiling was performed in human chondrocytes. This study reveals association between methylation of specific CpG sites and chondrocyte age. We also determined the putative binding targets of STAT3, a key age-patterned transcription factor in fetal chondrocytes and genetic ablation of STAT3 induced a global genomic hypermethylation. Moreover, an epigenetic clock built for adult human chondrocytes revealed that exposure of aged adult human chondrocytes to STAT3 agonist, decreased epigenetic age. Taken together, this work will serve as a foundation to understand development and aging of chondrocytes with a new perspective for development of rejuvenation agents for synovial joints.

Competing Interest Statement

The authors have declared no competing interest.

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Genome-wide DNA methylation and multi-omics study of human chondrocyte ontogeny and an epigenetic clock analysis of adult chondrocytes
Arijita Sarkar, Siyoung Lee, Ruzanna Shkhyan, Nancy Q. Liu, Ben Van Handel, Jenny Magallanes, Youngjoo Lee, Litao Tao, Neil Segil, Jason Ernst, Steve Horvath, Denis Evseenko
bioRxiv 2021.08.02.454544; doi: https://doi.org/10.1101/2021.08.02.454544
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Genome-wide DNA methylation and multi-omics study of human chondrocyte ontogeny and an epigenetic clock analysis of adult chondrocytes
Arijita Sarkar, Siyoung Lee, Ruzanna Shkhyan, Nancy Q. Liu, Ben Van Handel, Jenny Magallanes, Youngjoo Lee, Litao Tao, Neil Segil, Jason Ernst, Steve Horvath, Denis Evseenko
bioRxiv 2021.08.02.454544; doi: https://doi.org/10.1101/2021.08.02.454544

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