A primate-specific alternative splicing of CCNE1 (pCCNE1) is an activator for evolutionally-gained enhancers [GRO-seq]

ABSTRACT: Divergence of protein and genetic function drives acquisition of novel phenotypes into organisms. Alternative splicing (AS) generates multiple proteins from a single gene and promotes the diversity of protein functions. The AS frequency has been increased throughout evolution and contributes to the complexity and the species specificity of cell and organ developmental programs. Retrotransposons (RTs) are major sources to configure the innovation and plasticity of the host genome and actively transcribed during human early development. However, it is not yet clear how the host genome responds to RTs in a reciprocal co-evolution. Here, we discovered that a primate-specific splicing variant of CCNE1 (pCCNE1) regulates primate-specific RTs to control human naïve pluripotency. Independent of the cell cycle regulatory function of ubiquitously-expressed CCNE1 (uCCNE1) with CDK2, we found that pCCNE1 competes with uCCNE1 in binding to the primate-specific RTs on a previously-uncharacterized DNA motif sequence. Especially, pCCNE1 preferentially activates hominid-specific SVA (SINE-VNTR-Alu) elements and synchronously upregulates their downstream host genes, which are uniquely expressed in human preimplantation embryos and naïve pluripotent stem cells (PSCs). Furthermore, pCCNE1 can activate dormant SVA (SINE-VNTR-Alu) enhancers and cooperatively activate their transcriptional regulatory activity with OCT4. Taken together, our results demonstrate that the evolutionary adaptation of human pluripotency via AS of CCNE1 contributes to the gain of novel molecular mechanisms for human-specific regulatory network, and how distinct phenotypes among species are created

ORGANISM(S): Homo sapiens

PROVIDER: GSE128438 | GEO | 2022/03/16

REPOSITORIES: GEO