The novel H2B variant, H2BW2, destabilizes nucleosomes and regulates gene expression during early human spermatogenesis

Abstract

In spennatogenesis, histones are gradually replaced by testis-specific histone variants, transition proteins. and later into protamine in elongating spermatids. H2BW2 is a testis-specific histone H2B variant mainly expressed in differentiated spermatogonia and primary spennatocytes. A lot of histone variants were known specifically to be expressed in some stages of spermatogenesis and perform unique functions. for example, H3T, TH2A, Th2B ... However. it remains little understood of the functions of H2BW2. In this study, we solved the structure of H2BW2-containing nucleosomes and revealed the underlying functions of this variant in human spermatogenesis. The H2BW2 nucleosome has a more relaxed structure, with a 35% reduction in its outer rips energy barrier, and only protects 125 ± 7 bp of the DNA from MNasc digestion. Such observed destabilization effects of H2BW2 are due to its extended N-terminal tail and changes in the ∝2 helix region, particularly region D85, and Q101 of H2BW2. Remarkably, we found H2BW2 is highly enriched in the TERRA promoter regions and is associated with higher TERRA expression and longer telomeres. Additionally. we found that older H2BW2-KO mice have significantly decreased TERRA expression, and progressive sperm motility was decreased while the frequency of abnormal sperm morphology was increased in the H2BW2-KO mice. Our results suggest that H2BW2 participates in the maintenance of telomere length by upregulating TERRA expression in early spermatogenesis and is necessary for sperm health and quality. Keywords: llislone Variants, H2BW2, H2BWT, TERRA. H2B. Telomere.

Date of Award	2023
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Toyotaka ISHIBASHI (Supervisor)