Histone Arginine Methyltransferase CARM1-Mediated H3R26me2 Is Essential for Morula-to-Blastocyst Transition in Pigs

Abstract

Coactivator-associated arginine methyltransferase 1 (CARM1) is involved in both establishment of first pluripotent lineage and pluripotency maintenance of embryonic stem cells (ESCs) in mice. However, the histone substrates and role of CARM1 in early embryonic development remain largely unknown. Here, we show that CARM1 specifically catalyzes H3R26me2 to promote porcine blastocyst formation. The putative histone substrates of CARM1, including H3R2me2, H3R17me2, and H3R26me2, are present in pig early embryos. The changes of CARM1 mRNA during early embryogenesis parallel that of H3R26me2. Functional studies using a combinational approach of chemical inhibition and RNA interference (RNAi) showed that catalytic activity inhibition of CARM1 protein or knockdown (KD) of CARM1 mRNA did not alter the levels of both H3R2me2 and H3R17me2, but significantly reduced H3R26me2 levels in porcine embryos. Furthermore, CARM1 inhibition or KD did not affect embryo development to the 2-cell, 4-cell, 8-cell, and morula stages, but severely compromised blastocyst development. CARM1 knocked down embryos that developed to the blastocyst stage had fewer total cells, inner cell mass (ICM), and trophectoderm (TE) cells. Mechanistically, single embryo RNA-sequencing analysis revealed that CARM1 KD altered the transcriptome characterized by downregulation of key genes associated with Hippo and PI3K-AKT signaling pathways. Taken together, these results demonstrate that CARM1 specifically catalyzes H3R26me2 in porcine embryos and participates in blastocyst development.

Quantitative proteomics reveals the dynamic proteome landscape of zebrafish embryos during the maternal-to-zygotic transition

“… 108 Carm1, which specifically catalyzes H3R26me2, was reported to participate in blastocyst development of porcine embryos. 109 Mier1 functions as a transcriptional repressor by recruitment of Hdac1 and has a similar expression change as Mta2, demonstrating that histone deacetylases (HDACs) are indispensable for ZGA by creating correct transcriptionally repressive and active states. 110 The functions of Mier1 and Nsd1b in regulating the MZT of zebrafish embryos are still not clear.…”

Protein arginine methyltransferase 4 modulates nitric oxide synthase uncoupling and cerebral blood flow in Alzheimer's disease

“…We have shown that DDAH2 protein is elevated in both cortical and hippocampal lysates in 3xTg-AD animals, which may be a compensatory response to increased ADMA production which was also observed in 3xTg-AD animals (Figure 3a,b). The most well-known function of PRMT4 is the methylation of histone H3 (Cao et al, 2021). The role of PRMT 4 in the central nervous system is primarily involved in the development of astroglial and oligodendritic cells (Selvi et al, 2015).…”

The Dynamics of Histone Modifications during Mammalian Zygotic Genome Activation

“…The asymmetrical distribution of H3R26me2 in blastomeres is detected in embryos as early as the four-cell stage [153]. Blastomeres with higher levels of CARM1 and H3R26me2 contribute more significantly to the formation of the ICM [159]. Furthermore, higher levels of H3R26me2 enhance the expression of pluripotent genes and facilitate Sox2 binding to its targets, contributing to ICM specification.…”

“…Furthermore, higher levels of H3R26me2 enhance the expression of pluripotent genes and facilitate Sox2 binding to its targets, contributing to ICM specification. Additionally, CARM1 overexpression can increase the frequency of asymmetric cell divisions, leading cells to adopt a more internal position in the embryo [159]. Alongside CARM1, another chromatin regulator named PR domain-containing 14 (PRDM14) is also asymmetrically expressed in four-cell embryos, thus modulating the level of H3R26me2 to favor contribution to the ICM [160][161][162].…”