Abstract:
BACKGROUND:Altering the biochemical makeup of chromatin by the incorporation of histone variants during development represents a key mechanism in regulating gene expression. The histone variant H2A.B, H2A.B.3 in mice, appeared late in evolution and is most highly expressed in the testis. In the mouse, it is encoded by three different genes. H2A.B expression is spatially and temporally regulated during spermatogenesis being most highly expressed in the haploid round spermatid stage. Active genes gain H2A.B where it directly interacts with polymerase II and RNA processing factors within splicing speckles. However, the importance of H2A.B for gene expression and fertility are unknown. RESULTS:Here, we report the first mouse knockout of this histone variant and its effects on fertility, nuclear organization, and gene expression. In view of the controversy related to the generation of off-target mutations by gene editing approaches, we test the specificity of TALENs by disrupting the H2A.B multi-copy gene family using only one pair of TALENs. We show that TALENs do display a high level of specificity since no off-target mutations are detected by bioinformatics analyses of exome sequences obtained from three consecutive generations of knockout mice and by Sanger DNA sequencing. Male H2A.B.3 knockout mice are subfertile and display an increase in the proportion of abnormal sperm and clogged seminiferous tubules. Significantly, a loss of proper RNA Pol II targeting to distinct transcription-splicing territories and changes to pre-mRNA splicing are observed. CONCLUSION:We have produced the first H2A.B knockout mouse using the TALEN approach.
journal_name
Genome Bioljournal_title
Genome biologyauthors
Anuar ND,Kurscheid S,Field M,Zhang L,Rebar E,Gregory P,Buchou T,Bowles J,Koopman P,Tremethick DJ,Soboleva TAdoi
10.1186/s13059-019-1633-3subject
Has Abstractpub_date
2019-01-31 00:00:00pages
23issue
1eissn
1474-7596issn
1474-760Xpii
10.1186/s13059-019-1633-3journal_volume
20pub_type
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