Cytosine DNA methylation is a heritable epigenetic mark present in many eukaryotes. The mammalian genome
undergoes tightly regulated global demethylation early development where faithfully inherited DNA methylations
are essential. In adult soma, while DNA methylation is largely stable, its aberrations have been widely observed
in aged and malignant tissues. Under these conditions, broad hypomethylated domains have been observed at
gene deserts and genomic repeats, a phenomenon linked to excessive proliferations. In the meantime, focal
hypermethylation occurs at lineage specific promoters, accompanied by widespread methylation variations at
conserved regulatory loci. The molecular basis and functional consequences for these DNA methylation
abnormality in adult tissues remain poorly understood.
In the current study, we investigate the role of DNA methylation in determining adult stem cell fates under
homeostasis and upon stress. In particular, we focus on the regulation of retrotransposons (RTs) by DNA
methylation and how their impact adult stem cell function. Differing from tandem repeats in the centromere and
telomere that are constitutively heterochromatin, RTs are interspersed genomic repeats that exist in both
heterochromatin and euchromatin state. Compared to protein-coding genes comprising 1.5% of the genome,
RTs constitute 40% of the genome and exert many regulatory functions, but are understudied due to their
sequence repetitiveness and less conserved nature. During pre-implantation, RTs residing in the
heterochromatin are transiently derepressed due to global demethylation and play an essential role in embryonic
development. In adult somatic tissues, RTs are largely suppressed but become aberrantly induced when
heterochromatin is destabilized, such as during aging and cancer. What pathways control RT levels in adult
tissues, their impact on lineage gene expressions, and their physiological role under homeostasis and upon
stress remain unclear.
To address these questions, we use mouse skin as our model that harbors well-characterized, highly accessible,
and genetically amenable adult stem cells. Epidermal and hair follicle stem cells in the skin fuel the homeostatic
postnatal remodeling, drive wound induced regeneration, and undergo functional decline during aging. By using
genetic models lacking what we have found to be a crucial epigenetic repressor of RTs in adult skin, we examine
(1) the molecular basis for DNA and histone methylation mediated RT silencing, and (2) the mechanism by which
DNA methylation and RT dynamics regulate adult stem cell fate decision in a physiological setting. We
hypothesize that DNA methylation at RTs could either locally impact neighbor gene expressions or titrate rate
limiting methylation machinery to regulate lineage gene levels at a distance, both of which contributing to adult
stem cell fate decisions. Our study will provide insights into the molecular interconnection between euchromatin
and heterochromatin in the context of adult stem cell fate decisions and tissue fitness.
