Biology subjects

Niloy, A. J.

Publications and source records attributed to Niloy, A. J..

3 recordsLinked to original sources

bioRxiv2025

Divergent roles of DNA methylation, TRIM28, and p53 surveillance in human embryonic and trophoblast stem cells

Transcriptional regulation of transposons and genes by TRIM28 and 5mC is critical for proper mammalian embryonic development, but the specific roles for these mediators in human embryonic and placental lineage remain unclear. We find that loss of TRIM28 has a limited effect on global transposon expression and instead results in upregulation of genes proximal to TRIM28-bound Long Terminal Repeats (LTRs) in both human trophoblast stem cells (hTSCs) and human embryonic stem cells (hESCs). MER11A elements show especially strong regulatory importance in hTSCs: these elements are bound by both TRIM28 and placental transcription factors and show both heterochromatic and euchromatic features. Some genes are positively regulated by MER11A elements in hTSC basal state, while other MER11A-proximal genes show upregulation only upon TRIM28 deletion. By contrast, loss of DNA methylation in hESCs or hTSCs leads to a global increase in transposon expression. While many genic 5mC targets are shared in hESCs and hTSCs, we also observe evidence that a handful of genes important for somatic development are repressed by 5mC in trophoblast, while a small parallel set of placental genes are repressed by methylation in embryonic tissue. Interestingly, loss of DNMT1 causes hESCs to be rapidly lost from culture in a TP53 and mitotic surveillance checkpoint-dependent manner, while hTSCs show little p53 response to DNMT1 loss or DNA damage generally, instead showing gradual mitotic defects and aneuploidy and slow loss from culture. This discrepancy may explain the higher frequency of karyotypic abnormality found in human placental cells. Together, this study charts the role of TRIM28 and DNA methylation in regulating embryonic and placental transcription and demonstrates divergent p53-dependent responses to genomic instability.

molecular biology↗

bioRxiv2025

Arginine methyltransferase PRMT1 equipoises trophoblast development to prevent early pregnancy loss

Abstract1-2% of all human pregnancies suffer from idiopathic recurrent pregnancy loss (RPL) and underlying molecular causes are poorly understood. Here we show that defective Protein Arginine Methyltransferase 1 (PRMT1) function in trophoblast progenitors is a molecular cause for early pregnancy failure. PRMT1 is conserved in trophoblast progenitors and conditional deletion of PRMT1 in mouse trophoblast progenitors arrests placenta and embryonic development leading to lethality [~]E7.5. Remarkably, a subset of idiopathic RPL is associated with loss of PRMT1 in cytotrophoblast progenitors (CTBs). Experiments with human trophoblast stem cells (hTSCs), derived from these RPL-patients as well as PRMT1-depleted hTSCs revealed that PRMT1 is crucial for trophoblast progenitors self-renewal. Employing RNA-seq and CUT&RUN-sequencing in hTSCs, CTBs and primary mouse trophoblast progenitors we discover that PRMT1 promotes transcription of trophoblast stem-state regulators, like TEAD4 and MYBL2, by directly enriching histone H4 arginine 3 asymmetric di-methylation (H4R3Me2a) at their chromatin loci. PRMT1 is also essential for extravillous trophoblast (EVT) development during human placentation, while loss of PRMT1 in hTSCs spontaneously promotes syncytiotrophoblast (STB) differentiation. Our findings indicate that PRMT1 is an epigenetic governor that orchestrates mammalian trophoblast development and implicate the therapeutic potential of targeting the PRMT1-H4R3Me2a axis to mitigate early pregnancy loss.

developmental biology↗

bioRxiv2024

METTL3 shapes m6A epitranscriptomic landscape for successful human placentation

Methyltransferase-like 3 (METTL3), the catalytic enzyme of methyltransferase complex for m6A methylation of RNA, is essential for mammalian development. However, the importance of METTL3 in human placentation remains largely unexplored. Here, we show that a fine balance of METTL3 function in trophoblast cells is essential for successful human placentation. Both loss-of and gain-in METTL3 functions are associated with adverse human pregnancies. A subset of recurrent pregnancy losses and preterm pregnancies are often associated with loss of METTL3 expression in trophoblast progenitors. In contrast, METTL3 is induced in pregnancies associated with fetal growth restriction (FGR). Our loss of function analyses showed that METTL3 is essential for the maintenance of human TSC self-renewal and their differentiation to extravillous trophoblast cells (EVTs). In contrast, loss of METTL3 in human TSCs promotes syncytiotrophoblast (STB) development. Global analyses of RNA m6A modification and METTL3-RNA interaction in human TSCs showed that METTL3 regulates m6A modifications on the mRNA molecules of critical trophoblast regulators, including GATA2, GATA3, TEAD1, TEAD4, WWTR1, YAP1, TFAP2C and ASCL2, and loss of METTL3 leads to depletion of mRNA molecules of these critical regulators. Importantly, conditional deletion of Mettl3 in trophoblast progenitors of an early post-implantation mouse embryo also leads to arrested self-renewal. Hence, our findings indicate that METLL3 is a conserved epitranscriptomic governor in trophoblast progenitors and ensures successful placentation by regulating their self-renewal and dictating their differentiation fate.

developmental biology↗