Foxd3 controls heterochromatin‐mediated repression of repeat elements and 2‐cell state transcription. (4th October 2021) - Puri, Deepika
Abstract: Repeat element transcription plays a vital role in early embryonic development. The expression of repeats such as MERVL characterises mouse embryos at the 2‐cell stage and defines a 2‐cell‐like cell (2CLC) population in a mouse embryonic stem cell culture. Repeat element sequences contain binding sites for numerous transcription factors. We identify the forkhead domain transcription factor FOXD3 as a regulator of major satellite repeats and MERVL transcription in mouse embryonic stem cells. FOXD3 binds to and recruits the histone methyltransferase SUV39H1 to MERVL and major satellite repeats, consequentially repressing the transcription of these repeats by the establishment of the H3K9me3 heterochromatin modification. Notably, depletion of FOXD3 leads to the de‐repression of MERVL and major satellite repeats as well as a subset of genes expressed in the 2‐cell state, shifting the balance between the stem cell and 2‐cell‐like population in culture. Thus, FOXD3 acts as a negative regulator of repeat transcription, ascribing a novel function to this transcription factor. SYNOPSIS: The forkhead domain transcription factor FOXD3 is involved in the heterochromatin‐mediated repression of major satellite repeats and MERVL, thereby counteracting the transcription of 2‐cell state promoting genes in mouse embryonic stem cells. FOXD3 binds to repeat elements, especially major satellite repeats (MSRs) and MERVL in mouse embryonic stem cells. FOXD3 depletion leads to an upregulation of MSRs, MERVL and a subset of 2‐cell state genes. FOXD3 regulates repeat transcription by recruiting the heterochromatin histone methyltransferase SUV39H1. SUV39H1 recruitment establishes repressive H3K9me3 marks on MSRs and MERVL. Abstract : The forkhead domain transcription factor FOXD3 is involved in the heterochromatin‐mediated repression of major satellite repeats and MERVL, thereby counteracting the transcription of 2‐cell state promoting genes in mouse embryonic stem cells.