Heterochromatin Protein 1 (HP1) is a protein family of epigenetic modifiers that are
integral units of heterochromatin establishment with three mammalian isoforms
HP1α, HP1β and HP1γ. All three isoforms are found in heterochromatic regions where
they assist with chromatin compaction and gene silencing, yet, HP1γ is also enriched
on euchromatic regions with a suggestive gene activating role. In mice, HP1γ has been
shown to influence genes that differ between the sexes, nonetheless, the implications
of this sexual dimorphism and the molecular mechanisms underlying it are poorly
understood. Here, I show that HP1γ is important for male cell proliferation and its
absence causes earlier onset of cellular senescence in both sexes. The effect of HP1γ
loss is further reflected in male embryo growth rate. Cleavage under targets and
release using nuclease (CUT & RUN) analysis revealed that HP1γ is binding on genes
differentially expressed among the sexes affecting their expression. Preliminary data
using Super-Low Input Carrier Cap analysis of gene expression (SLIC-CAGE) suggests
that HP1γ most likely does not regulate cryptic transcription in mice. HP1γ was also
enriched on repetitive DNA sequences at the end of chromosomes termed telomeres.
Given the recruitment of HP1γ at telomeres for heterochromatin formation and the
direct link between senescence and telomere length, we examined the role of this
factor on telomere maintenance. Loss of mouse HP1γ leads to a downregulation of
various telomere and telomere-accessory transcripts, including shelterin protein
TRF1. This transcriptional and protein downregulation is associated with increased
telomere replication stress and DNA damage, both effects more profound in females.
My analysis suggests that the source of the impaired telomere replication is the
increase in telomeric DNA:RNA hybrids due to the upregulation of TElomeric Repeatcontaining
RNA (TERRA) arising from mouse chromosome 18 and chromosome X.
Overall, this PhD thesis showcases the important role of HP1γ on sexual dimorphism
and telomere stability during early mouse development.