YTHDC2 is essential for pachytene progression and prevents aberrant microtubule-driven telomere clustering in male meiosis
Rong Liu,
Seth D. Kasowitz,
David Homolka,
N. Adrian Leu,
Jordan T. Shaked,
Gordon Ruthel,
Devanshi Jain,
Huijuan Lin,
Scott Keeney,
Mengcheng Luo,
Ramesh S. Pillai,
P. Jeremy Wang
Affiliations
Rong Liu
School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei Province, China; Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
Seth D. Kasowitz
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
David Homolka
Department of Molecular Biology, Science III, University of Geneva, CH-1211 Geneva 4, Switzerland
N. Adrian Leu
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
Jordan T. Shaked
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
Gordon Ruthel
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
Devanshi Jain
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA; Department of Genetics, Rutgers University, Piscataway, NJ, USA
Huijuan Lin
School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei Province, China; Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
Scott Keeney
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
Mengcheng Luo
School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei Province, China
Ramesh S. Pillai
Department of Molecular Biology, Science III, University of Geneva, CH-1211 Geneva 4, Switzerland
P. Jeremy Wang
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA; Corresponding author
Summary: Mechanisms driving the prolonged meiotic prophase I in mammals are poorly understood. RNA helicase YTHDC2 is critical for mitosis to meiosis transition. However, YTHDC2 is highly expressed in pachytene cells. Here we identify an essential role for YTHDC2 in meiotic progression. Specifically, YTHDC2 deficiency causes microtubule-dependent telomere clustering and apoptosis at the pachytene stage of prophase I. Depletion of YTHDC2 results in a massively dysregulated transcriptome in pachytene cells, with a tendency toward upregulation of genes normally expressed in mitotic germ cells and downregulation of meiotic transcripts. Dysregulation does not correlate with m6A status, and YTHDC2-bound mRNAs are enriched in genes upregulated in mutant germ cells, revealing that YTHDC2 primarily targets mRNAs for degradation. Furthermore, altered transcripts in mutant pachytene cells encode microtubule network proteins. Our results demonstrate that YTHDC2 regulates the pachytene stage by perpetuating a meiotic transcriptome and preventing microtubule network changes that could lead to telomere clustering.
