The elongation factor Elof1 is required for mammalian gastrulation

Abstract

Despite having been sequenced over a decade ago, the functional significance of much of the mammalian genome remains unknown. The mouse has become the preeminent mammalian model for identifying endogenous gene function in vivo . Here we characterize the phenotype of a loss-of function allele for the evolutionarily conserved transcription factor, Elongation Factor Homolog 1 (Elof1). Recent work utilizing the yeast homolog, Elf1, has demonstrated that Elf1 associates with the RNA polymerase II complex to promote elongation by relieving the association of the template DNA strand with bound histones. Loss of Elof1 results in developmental delay and morphological defects during early mouse development resulting in peri-gastrulation lethality. Although Elof1 is highly conserved we observe tissue specific expression during gastrulation and in adult murine tissues, suggesting there may be other genes with similar function in diverse tissues or that mElof1 has adopted lineage specific functions. To better understand its function in mammalian transcription, we examined splice variants and find that Elof1 regulates mutually exclusive exon use in vivo . Distinct from what has been demonstrated in yeast, we demonstrate that Elof1 is essential for viability during mammalian gastrulation which may be due to a role mediating tissue specific exclusive exon use, a regulatory function unique to higher eukaryotes.

Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

“…Interestingly, while the interaction of most TC-NER factors with elongating Pol II is strongly increased upon DNA damage 1 , 7 , 23 , ELOF1 is an intrinsic part of the elongating complex in unperturbed conditions, where it stimulates transcription elongation ( Fig.2 ). Its dual function as an elongation and repair factor can be the cause of the embryonic lethality observed in ELOF1 KO mice 44 and may explain why thus far no ELOF1 mutations were found in TC-NER-related syndromes 4 .…”

Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

“…2). Its dual function as an elongation and repair factor can be the cause of the embryonic lethality observed in ELOF1 KO mice 61 and may explain why thus far no ELOF1 mutations were found in TC-NER related syndromes, something commonly observed for other TC-NER factors 12 . The role of ELOF1 in TC-NER is highly conserved, also in yeast in which TC-NER is differently organized.…”

“…5). The chromatin binding of the transcription machinery and the inability to clear Pol II from the DNA is assumed to play an important role in the onset of transcriptionreplication conflicts 8,61,64 . Even though CSB and ELOF1 depletion had similar effects on the prolonged binding of Pol II upon DNA damage (Fig.…”

Dissecting the Complexity of Early Heart Progenitor Cells

“…Removal of the transcription factors Etv2 or Npas4l yields embryos that lack endothelial cells but undergo gastrulation normally, forming a heart tube without ECs [99,100]. To date, no genetic manipulation produced embryos that gastrulate but fail to form CMs: all mutants without CMs also fail to gastrulate, lacking all anterior mesoderm tissues [101][102][103][104][105][106]. In some of these, stuck mesodermal cells express CM differentiation markers [106] or even form bilateral heart tubes [9].…”