Trophoblast PR-SET7 dysfunction induces viral mimicry response and necroptosis associated with recurrent miscarriage

Abstract

Recurrent miscarriage (RM) is a distressing pregnancy complication. While the etiology of RM remains unclear, growing evidence has indicated the relevance of trophoblast impairment to the pathogenesis of RM. PR-SET7 is the sole enzyme catalyzing monomethylation of H4K20 (H4K20me1) and has been implicated in many pathophysiological processes. However, how PR-SET7 functions in trophoblasts and its relevance to RM remain unknown. Here, we found that trophoblast-specific loss of Pr-set7 in mice led to defective trophoblasts, resulting in early embryonic loss. Mechanistic analysis revealed that PR-SET7 deficiency in trophoblasts derepressed endogenous retroviruses (ERVs), leading to double-stranded RNA stress and subsequent viral mimicry, which drove overwhelming interferon response and necroptosis. Further examination discovered that H4K20me1 and H4K20me3 mediated the inhibition of cell-intrinsic expression of ERVs. Importantly, dysregulation of PR-SET7 expression and the corresponding aberrant epigenetic modifications were observed in the placentas of RM. Collectively, our results demonstrate that PR-SET7 acts as an epigenetic transcriptional modulator essential for repressing ERVs in trophoblasts, ensuring normal pregnancy and fetal survival, which sheds new light on potential epigenetic causes contributing to RM.

PR-SET7 epigenetically restrains uterine interferon response and cell death governing proper postnatal stromal development

“…Therefore, ERVs are tightly regulated by host surveillance mechanisms, including DNA methylation, histone modifications (e.g., H3K9me3 and H4K20me3) and RNA modifications (e.g., m6A), either individually or concurrently 34 . In addition to H3K9me3 and H4K20me3, a recent report demonstrated that PR-SET7-mediated H4K20me1 also participated in the transcriptional silencing of ERVs in trophoblast cells 20 , and we discovered a similar epigenetic regulatory mechanism in the neonatal uterus in the present study. Further investigations are required to interrogate whether H4K20me1 mediates the repression of ERVs alone or via the interplay with other epigenetic regulatory machinery during postnatal uterine development.…”

“…The pathophysiological significance of PR-SET7-mediated H4K20me1 in female reproduction has been reported. Trophoblast-specific deletion of Pr-set7 resulted in ERV derepression, viral mimicry responses, and necroptosis, which shed light on the potential etiology and pathogenesis of recurrent miscarriage 20 . Meanwhile, uterine PR-SET7 deficiency limited uterine epithelial population growth due to impaired DNA damage repair and severe epithelial cell apoptosis, which hampered gland formation in neonatal mice 26 .…”

“…PR-SET7, an evolutionarily conserved histone methyltransferase, is the sole enzyme known to catalyze H4K20me1, which serves as the substrate for H4K20me2/3 12 , 13 . In addition to its well-accepted canonical functions in cell cycle progression, DNA damage repair, and gene transcriptional regulation 14 – 19 , PR-SET7-mediated H4K20me1 was recently demonstrated to repress the intrinsic expression of endogenous retroviruses (ERVs), contributing to the maintenance of genomic stability 20 . Accumulating evidence has uncovered the indispensable roles of PR-SET7 and H4K20me1 in diverse physiological and pathological processes during the development and homeostasis of multiple organs and tissues 21 – 25 .…”

SETD8 inhibition targets cancer cells with increased rates of ribosome biogenesis

“…Finally, and despite of having worked on characterizing the compounds presented here, and on the potential efficacy of SETD8 inhibitors for cancer therapy, we would also want to add a word of caution on this regard. SETD8 is essential for mouse development [19], and has also been shown to be essential in multiple tissue-specific knockout models [30–35]. Data available at the cancer dependency map (DEPMAP) [36] indicate that this essentiality occurs at the cell level, and likely to be found in all cell types.…”

Basic Research Advances in China on Embryo Implantation, Placentation, and Parturition

“…The deficiency of Pr-set7, the sole enzyme catalyzing H4K20me1, leads to ERV derepression, double-stranded RNA stress, overwhelming viral mimicry responses, and trophoblast necroptosis. 72 The placenta serves as an endocrine organ and produces various hormones, including human chorionic gonadotropin, prolactin, estrogen, and progesterone, to guarantee successful pregnancy maintenance. 7 A recent study showed an uncharacterized role of RGS2 in the production of estrogen by the placenta.…”