Isojima, T. | Search bioRxiv

bioRxiv2023

DNA methylation signature in NSD2 loss-of-function variants appeared similar to that in Wolf-Hirschhorn syndrome

PurposeWolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome caused by the hemizygous deletion of the distal short arm of chromosome 4 where NSD2 is, reportedly exhibits specific DNA methylation signatures in peripheral blood cells. However, responsible genomic loci for signatures are unreported. The objective of the study is to define the loci of WHS-related DNA methylation signatures and to explore the role of NSD2 for the signatures. MethodsWe conducted genome-wide methylation analysis of individuals with WHS or NSD2 variants using array. We studied genome-edited knock in mice or induced pluripotent stem cells to explore the function of NSD2 variants which are observed in congenital anomaly cases. ResultsThree undiagnosed cases with NSD2 variants showed WHS-related DNA methylation signatures. These variants were validated to be NSD2 loss-of-function in induced pluripotent stem cells or genome-edited knock-in mice. p.Pro905Leu variant decreased Nsd2 protein levels, and changed Histone H3-Lysine 36 demethylation levels in similar way in the same genomic regions as Nsd2 knock out mice regulated. Nsd2 knock out mice exhibited common DNA methylation changes. ConclusionThese results revealed that WHS-related DNA methylation signatures are dependent on NSD2 dysfunction and are useful in diagnosing NSD2 variants of unknown significance.

genetics↗

bioRxiv2020

Dmp1Cre-directed knockdown of PTHrP in murine decidua is associated with increased bone width and a life-long increase in strength specific to male progeny

Parathyroid hormone related-protein (PTHrP) is a pleiotropic regulator of tissue homeostasis. In bone, knockdown in osteocytes by Dmp1Cre-targeted deletion causes osteopenia and impaired strength. We report that this outcome depends on parental genotype. Adult Dmp1Cre.Pthlhf/f mice from homozygous parents (Dmp1Cre.Pthlhf/f(hom)) have stronger bones, with 40% more trabecular bone mass and 30% greater femoral width than controls. At 12 days old, greater bone width was also found in male and female Dmp1Cre.Pthlhf/f(hom) mice, but not in gene-matched mice from heterozygous parents, suggesting a maternal influence before weaning. Milk PTHrP levels were normal, but decidua from mothers of Dmp1Cre.Pthlhf/f(hom) mice were smaller, with low PTHrP levels. Moreover, Dmp1Cre.Pthlhf/f(hom) embryonic bone was more mineralized and wider than control. We conclude that Dmp1Cre leads to gene recombination in decidua, and that decidual PTHrP influences decidual cell maturation and limits embryonic bone growth. This identifies a maternal-derived developmental origin of adult bone strength.

cell biology↗