Project description:A massively expanded outer subventricular zone (OSVZ) in the primate and human has been proposed for generating majority of neocortical neurons, which consists of basally located radial glia cells. Previous studies with various strategies have tried to recognize genes specifically expressed in those cells; however, the molecular and cellular features of these cells still remain uncertain. By profiling gene expression across single cells isolated from cellular anatomy location and subtype sorting, we identified a primate-specific gene TMEM14B as a novel marker for basally located radial glia. Expression of TMEM14B induced dramatic increase in the number of radial glial and OSVZ region. Finally, we found that OSVZ progenitor’s extensive proliferative potential was up regulated through IQGAP1 phosphorylation and nuclear translocation, and remarkably, led to the gyrification in postnatal mouse. These results highlight that evolutionary expansion promoted by primate-specific genes enabling the evolutionary expansion and folding of the human neocortex.
Project description:The spermatogonial stem cells (SSCs) niche is critical for SSC maintenance and the subsequent spermatogenesis. Numerous reproductive hazards impair the SSC niche, thereby result in aberrant SSC self-renewal and male infertility. However, promising agents targeting the impaired SSC niche to promote SSC self-renewal are still limited. Here, we screen out and assess the effects of Lovastatin on the self-renewal of mouse spermatogonial stem cells (mSSCs). Mechanistically, Lovastatin promotes the self-renewal of mSSCs and inhibits its inflammation and apoptosis through the regulation of isoprenoid intermediates. Likewise, other statins exhibit similar effects on SSC self-renewal. Remarkably, the treatment by Lovastatin could promote the self-renewal of mSSCs in the male gonadotoxicity model generated by busulfan injection. Noteworthy, we demonstrate that Lovastatin could significantly enhance the self-renewal of in vitro cultured primate SSCs. Collectively, our findings uncover that lovastatin could promote the self-renewal of both murine and primate SSCs and have implications for the treatment of certain male infertility using small compounds.
Project description: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
Project description: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
Project description: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
Project description:Induced pluripotent stem cells (iPSCs) are regarded as a central tool to understand human biology in health and disease. Similarly, iPSCs from closely related species should be a central tool to understand human evolution and to identify conserved and variable patterns of iPSC disease models. Here, we have generated human, gorilla, bonobo and cynomolgus monkey iPSCs. We show that these cells are well comparable in their differentiation potential and generally similar to human, cynomolgus and rhesus monkey embryonic stem cells (ESCs). RNA sequencing reveals that expression differences among clones, individuals and stem cell type are all of very similar magnitude within a species. In contrast, expression differences between closely related primate species are three times larger and most genes show significant expression differences among the analysed species. However, pseudogenes differ more than twice as much, suggesting that evolution of expression levels in primate stem cells is rapid, but constrained. These patterns in pluripotent stem cells are comparable to those found in other tissues except testis. Hence, primate iPSCs reveal insights into general primate gene expression evolution and should provide a rich source to identify conserved and species-specific gene expression patterns for cellular phenotypes. Contributors: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany We used expression profiling to characterize five gorilla, two bonobo and three macaque iPS clones as well as three iPS clones from two human individuals, three human embryonic stem (ES) cell lines and three macaque ES cell lines. We generated tagged RNA-Seq libraries from these 19 samples including four technical replicates (23 samples). Over 100 million single end reads were generated on the Illumina platform.
Project description:Messenger RNA secondary structure is critical to all aspects of post-transcriptional regulation. However, the global regulatory and evolutionary significance of mRNA secondary structure remains largely illusive. Here, we describe a transcriptome-wide analysis of RNA secondary structure in humans and two non-human primates, based on a high-throughput, nuclease-mediated, structure mapping approach. Using this methodology, we uncover global patterns of mRNA secondary structure, which we find to be conserved through primate evolution. We provide evidence for secondary structure-based regulatory pathways, which impact on gene expression through associations with translational machinery and RNA-binding proteins, including components of the microprocessor complex. Our results lend support to an unexpected, conserved mechanism by which highly structured regions of mRNAs serve as processing sites for small RNAs, resulting in subsequent turnover. Global mRNA secondary structure analysis in primate transcriptomes using high-throughput, nuclease-mediated, structure mappinng approaches of dsRNA-seq and ssRNA-seq, also with polyA+ mRNA-seq, smRNA-seq (small RNA), and genome-wide mapping of uncapped and cleaved transcripts (GMUCT); these NGS-seq experiments were carried out in three primate brains as well as three different cell lines, both in in vitro and in vivo.