An epigenetic timer of gestation length in mice [CUT&RUN]

Current efforts investigating parturition timing mechanisms have focused on the proximal triggers of labor onset generated in late gestation. By studying the delayed parturition phenotype of mice with uterine fibroblast deficiencies in the histone H3K37me3 demethylase KDM6B, we provide evidence that parturition timing is regulated by events that take place in early pregnancy. Immediately after copulation, uterine fibroblasts engage in a locus-specific, epigenetic program that abruptly adjusts H3K27me3 levels across their genome. In the absence of KDM6B, many of the adjusted loci over-accumulate H3K27me3. This over-accumulation leads to nearby genes being misexpressed in mid-to-late gestation, a delayed effect partly attributable to a second locus-specific but KDM6B-independent process initiated within uterine fibroblasts soon after implantation. This second process employs progressive H3K27me3 loss to temporally structure post-midgestational patterns of gene induction. Further dissection of the ways uterine programming controls parturition timing may have relevance to human pregnancy complications such as preterm labor. Overall design: H3K27me3 CUT&RUN was performed on myometrium/endometrium fibroblasts from control and Pgr-cre Kdm6b floxed mice on GD0.5, GD5.5, GD8.5, GD14.5, and GD18.5. Additionally, H3K27me3 CUT&RUN was performed on myometrium/endometrium fibroblasts from B6CBAF1/J from GD0.5, GD5.5 after natural mating, or GD5.5 after mating with a vasectomized male. Data also includes H3K27me3 CUT&RUN on B6CBAF1/J non-pregnant mice treated with progesterone for 3 days prior to sacrifice.