EMBL Seminars

Abstract
Development is driven by a sequence of molecularly interconnected transcriptional, epigenetic, and metabolic changes. Specific metabolites, like α-ketoglutarate (αKG), function as signalling molecules affecting the activity of chromatin modifying enzymes. It remains unclear, how such non-canonical function of metabolism coordinates specific cell-state changes especially in early development. Here we uncover that when naive human embryonic stem cells (nESC) are induced towards human trophoblast stem cells (hiTSC) a significant metabolic rewiring occurs, characterised by the accumulation of αKG. Published in vivo transcriptomic data further confirmed that metabolic rewiring likely takes place in the nascent trophectoderm (TE). We show that the intracellular αKG level is an important regulator of TE fate acquisition. Indeed, a dimethyl-αKG (dm-αKG) treatment of nESC increases their competence towards TE-like cells during hiTSC induction. Moreover, dm-αKG also increases the robustness of blastoid polarisation and TE maturation. Surprisingly, dm-αKG treatment does not affect global histone methylation levels in nESC, but rather leads to decreased acetyl-CoA levels, reduced histone acetyltransferase (HAT) activity and weakening of the pluripotency network. Further functional assays confirmed that both HAT inhibition and increased αKG level promote nESC competence towards TE but not other lineages e.g. primitive endoderm. We propose that an increased αKG level regulates pluripotency by reducing acetylation, thus creating a positive feedback loop promoting the induction of TE fate.

Abstract
Drastic epigenetic reprogramming occurs during mammalian early embryogenesis. Deciphering the molecular events underlying these processes is crucial for understanding how epigenetic information is transmitted between generations and how life really begins. Probing these questions was previously hindered by the scarce experimental materials that are available in early development. By developing a set of ultra-sensitive chromatin analysis technologies, we investigated chromatin reprogramming during early mouse development for chromatin accessibility, histone modifications, and 3D architecture. These studies unveiled highly dynamic and non-canonical chromatin regulation during maternal-to-zygotic transition and zygotic genome activation (ZGA). However, how ZGA is kickstarted and how the early development program is progressively driven by transcription factors (TFs) remain enigmatic. Recently, we identified key TFs that act at the onset of ZGA, and those that connect ZGA to the first cell fate commitment. In this talk, I will discuss how TFs and epigenetic factors cooperatively establish embryonic program and restore the embryonic epigenomes when the life begins.