Biology subjects

Sun, M.-a.

Publications and source records attributed to Sun, M.-a..

3 recordsLinked to original sources

bioRxiv2022

Prevalent regulation of GATA2/3 and MSX2 on endogenous retrovirus-derived regulatory elements in human trophoblast stem cells

The placenta is an organ with extraordinary phenotypic diversity in eutherian mammals. Recent evidence suggests that numerous human placental enhancers are evolved from lineage-specific insertions of endogenous retroviruses (ERVs), yet the transcription factors (TFs) underlying their regulation remain largely elusive. Here, by first focusing on MER41, a primate-specific ERV family previously linked to placenta and innate immunity, we uncover the binding motifs of multiple crucial trophoblast TFs (GATA2/3, MSX2, GRHL2) in addition to innate immunity TFs STAT1 and IRF1. Integration of ChIP-Seq data confirms the binding of GATA2/3, MSX2 and their related factors on the majority of MER41-derived enhancers in human trophoblast stem cells (TSCs). Notably, MER41-derived enhancers that are constitutively active in human TSCs are distinct from those activated upon interferon stimulation, which is determined by the binding of relevant TFs and their sub-family compositions. We further demonstrate that GATA2/3 and MSX2 have prevalent binding on numerous other ERV families - indicating their broad impact on ERV-derived enhancers. Functionally, the derepression of many syncytiotrophoblast genes after disruption of MSX2 is likely to be mediated by regulatory elements derived from ERVs - suggesting ERVs are also important for mediating transcriptional repression. Overall, this study characterized the prevalent regulation of GATA2/3, MSX2 and their co-factors on ERV-derived regulatory elements in human TSCs and provided mechanistic insights into the importance of ERVs in human trophoblast regulatory network.

evolutionary biology↗

bioRxiv2021

Homeobox transcription factor MNX1 is crucial for restraining the expression of pan-neuronal genes in motor neurons

Motor neurons (MNs) control muscle movement and are essential for breathing, walking and fine motor skills. Motor Neuron and Pancreas Homeobox 1 (MNX1) has long been recognized as a key marker of the MN lineage. Deficiency of the Mnx1 gene in mice results in early postnatal lethality - likely by causing abnormal MN development and respiratory malfunction. However, the genome-wide targets and exact regulatory function of Mnx1 in MNs remains unresolved. Using an in vitro model for efficient MN induction from mouse embryonic stem cells, we identified about six thousand MNX1-bound loci, of which half are conserved enhancers co-bound by the core MN-inducing factors ISL1 and LHX3, while the other half are promoters for housekeeping-like genes. Despite its widespread binding, disruption of Mnx1 affects the activity of only a few dozen MNX1-bound loci, and causes mis-regulation of about one hundred genes, the majority of which are up-regulated pan-neuronal genes with relatively higher expression in the brain compared to MNs. Integration of genome-wide binding, transcriptomic and epigenomic data in the wild-type and Mnx1-disrupted MNs predicts that Pbx3 and Pou6f2 are two putative direct targets of MNX1, and both are homeobox transcription factors highly expressed in the central nervous system. Our results suggest that MNX1 is crucial for restraining the expression of many pan-neuronal genes in MNs, likely in an indirect fashion. Further, the rarity of direct targets in contrast to the widespread binding of MNX1 reflects a distinctive mode of transcriptional regulation by homeobox transcriptional factors.

molecular biology↗

bioRxiv2020

Deciphering the evolution of the transcriptional and regulatory landscape in human placenta

In mammals, the placenta mediates maternal-fetal nutrient and waste exchange and provides immunomodulatory actions that facilitate maternal-fetal tolerance. The placenta is highly diversified among mammalian species, yet the molecular mechanisms that distinguish the placenta of human from other mammals are not fully understood. Using an interspecies transcriptomic comparison of human, macaque, and mouse term placentae, we identified hundreds of genes with lineage-specific expression - including dozens that are placentally-enriched and potentially related to pregnancy. We further annotated the enhancers for different human tissues using epigenomic data and demonstrate that the placenta and chorion are unique in that their enhancers display the least conservation. We identified numerous lineage-specific human placental enhancers, and found they are highly overlapped with specific families of endogenous retroviruses (ERVs), including MER21A, MER4A/B and MER39B that were previously linked to immune response and placental function. Among these ERV families, we further demonstrate that MER41 insertions create dozens of lineage-specific Serum Response Factor (SRF) binding loci in human, including one adjacent to FBN2, a placenta-specific gene with increased expression in humans that produces the peptide hormone placensin to stimulate glucose secretion and trophoblast invasion. Our results demonstrate the prevalence of lineage-specific human placental enhancers which are frequently associated with ERV insertions and likely facilitated the lineage-specific evolution of the mammalian placenta.

evolutionary biology↗