Endogenous retrovirus control of calbindin is essential for human early embryogenesis

Abstract

The cis-regulatory potential of human endogenous retroviruses (HERVs) that have accumulated in our genome affects diverse host processes, including embryonic development and malignancy, where HERV epigenetic control is reduced. Non–small cell lung cancer optimal growth requires cancer cell–intrinsic expression of the calcium-binding protein calbindin under the control of a HERVH integrant on chromosome 8q21.3. Chimeric transcription of HERVH and CALB1, encoding calbindin, is also observed in human embryonic stem cells (ESCs), but its significance remained uncertain. Here, we show that HERVH integration on 8q21.3 during Homininae evolution coincides with acquisition of expression of CALB1 in preimplantation embryos. We further show that CALB1 expression is critical for human ESC growth and the prevention of cellular senescence and for the formation of ESC-derived preimplantation blastoids and postgastrulation amnioids. Thus, the co-option of HERVH 8q21.3 cis-regulatory activity in lung cancer may echo its essential requirement for human embryo development.