Description:

The Simpson Querrey Institute for Epigenetics presents:

Yejing Ge, PhD

Assistant Professor, Department of Cancer Biology
University of Texas, MD Anderson Cancer Center, Houston

"Dissect the Silencing and Pathogenic Mechanisms of Retrotransposons in Tissue Regeneration" 

Abstract:

Transposons are interspersed genomic repeats that constitute over 40% of the mammalian genome. While some transposons are co-opted for host benefits, others, if aberrantly reactivated, may lead to mutations, inflammations, and genome instability. Elevated transposon activities are widely observed in cancer and aging, though the extent to which they functionally contribute to disease is unclear, and their molecular trigger remains poorly defined.

Using a genetic mouse model lacking the histone methyltransferase SETDB1 in skin stem cells, we saw surge of endogenous retroviruses (ERVs, a type of retrotransposon) and assembly of virus-like particles. This led to stem cell exhaustion and hair loss, which can be reversed by antiviral drugs. Intriguingly, while ERVs were activated across the SETDB1-deficient skin, different subsets of stem cells responded in distinct ways. Epidermis and upper hair follicle (which form the skin barrier) mounted antiviral responses, whereas transient amplifying cells (involved in hair regeneration) experienced antiviral-independent replication stress. Both responses contributed to skin pathology. This compartmentalized response may confer evolutionary advantages, as barrier-interfacing progenitors can effectively mount antiviral attack, while hair-forming precursors are spared from the battle and prioritize tissue regeneration.

To dissect the physiological role of SETDB1, we saw its protein levels correlate with adult stem cell activation during the hair cycle. Genome wide DNA methylation assay revealed  interesting differences: while loss of DNMT1 led to global hypomethylation as expected, SETDB1 deletion caused selective demethylation at the reactivated ERVs. Meanwhile, 5-hydroxymethylation accumulated at these sites. Importantly, deletion of TET enzymes (on top of SETDB1 loss) reversed ERV reactivation, indicating that TET-mediated DNA hydroxymethylation is essential for ERV induction. Therefore, SETDB1 likely prevents TET activity at ERVs while allowing normal TET action at lineage-specific genes, thereby ensuring proper lineage progression. As TET-mediated DNA demethylation and ERV induction trigger replication stress, we speculate this chromatin checkpoint may minimize defective precursor cells from contributing to tissue regeneration.

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