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Dynamic Regulation of Histone H3 Methylation at Lysine 4 in Mammalian Spermatogenesis¹

Departments of Animal Science and Pharmacology and Therapeutics,³ McGill University, Montreal, Quebec, Canada H9X 3V9 Department of Public Health and Cell Biology,⁴ University of Rome Tor Vergata, 00133 Rome, Italy Laboratory of Neuroembryology,⁵ IRCCS Fondazione Santa Lucia, 00133 Rome, Italy Stem Cell Research Group, German Primate Center,⁶ 37077 Goettingen, Germany

ABSTRACT

Spermatogenesis is a highly complex cell differentiation process that is governed by unique transcriptional regulation and massive chromatin alterations, which are required for meiosis and postmeiotic maturation. The underlying mechanisms involve alterations to the epigenetic layer, including histone modifications and incorporation of testis-specific nuclear proteins, such as histone variants and protamines. Histones can undergo methylation, acetylation, and phosphorylation among other modifications at their N-terminus, and these modifications can signal changes in chromatin structure. We have identified the temporal and spatial distributions of histone H3 mono-, di-, and trimethylation at lysine 4 (K4), and the lysine-specific histone demethylase AOF2 (amine oxidase flavin-containing domain 2, previously known as LSD1) during mammalian spermatogenesis. Our results reveal tightly regulated distributions of H3-K4 methylation and AOF2, and that H3-K4 methylation is very similar between the mouse and the marmoset. The AOF2 protein levels were found to be higher in the testes than in the somatic tissues. The distribution of AOF2 matched the cell- and stage-specific patterns of H3-K4 methylation. Interaction studies revealed unique epigenetic regulatory complexes associated with H3-K4 methylation in the testis, including the association of AOF2 and methyl-CpG-binding domain protein 2 (MBD2a/b) in a complex with histone deacetylase 1 (HDAC1). These studies enhance our understanding of epigenetic modifications and their roles in chromatin organization during male germ cell differentiation in both normal and pathologic states.

AOF2/LSD1, epigenetics, gamete biology, histone epigenetics, spermatogenesis, testis

¹Supported by grants from NSERC (to S.K.), the Dr. L.J. Johnson Foundation (to S.K.), and the Lance Armstrong Foundation (to C.S.). M.G. is supported by a fellowship from the McGill Faculty of Agriculture and Environmental Sciences, McGill University, Montreal, Canada.

Correspondence: ²Sarah Kimmins, Department of Animal Science, McGill University, 21111 Lakeshore Rd, Ste-Anne-de-Bellevue, Montreal, QC, Canada H9X 3V9. FAX: 514 398 7964; e-mail: sarah.kimmins{at}mcgill.ca