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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

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

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

2022-03-16 | GSE128439 | GEO

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

2022-03-16 | GSE128437 | GEO

The dynamic reprogramming of H3K9me3 at hominoid-specific retrotransposons during early human development

Project description:Reprogramming of H3K9me3-dependent heterochromatin is required for early development. How H3K9me3 is involved in early human development is, however, largely unclear. Here, we resolve the temporal landscape of H3K9me3 during human preimplantation development and its regulation for diverse hominoid-specific retrotransposons. At the 8-cell stage, H3K9me3 reprogramming at hominoid-specific retrotransposons termed SINE-VNTR-Alu (SVA) facilitates interaction between certain promoters and SVA-derived enhancers, facilitating the zygotic genome activation. In trophectoderm, de novo H3K9me3 domains prohibit pluripotent transcription factors from binding on hominoid-specific retrotransposons-derived regulatory elements for inner cell mass (ICM)-specific genes. H3K9me3 re-establishment at SVA elements in ICM is associated with higher transcription of DNA damage repair genes, compared to naïve human pluripotent stem cells. Our data demonstrate that species-specific reorganization of H3K9me3-dependent heterochromatin at hominoid-specific retrotransposons plays important roles during early human development, shedding light on how the epigenetic regulatory network for early development has evolved in mammals.

2022-07-14 | GSE176016 | GEO

Genome and Transcriptome Analysis of X-Linked Dystonia Parkinsonism Cohort

Project description:<p>X-linked Dystonia-Parkinsonism (XDP) is a long-standing quandary in human disease genetics. XDP is predominantly observed on Panay island in the Philippines. This study is one of the first of its kind to interrogate an unsolved Mendelian disorder by integrating genome and transcriptome assembly methods using Illumina, 10X Genomics, Pacific Biosciences, and Agilent genome targeting technologies. These data provide strong evidence for a pathogenic link between a noncoding SVA retrotransposon and XDP. We demonstrate that this Mendelian disorder is associated with a sine-VNTR-Alu (SVA) retrotransposon that inserted into the TAF1 gene and is shared by all XDP probands, yet never observed in controls from worldwide populations. Transcriptome assembly in iPSC-derived neural stem cells (NSCs) and neurons revealed that this SVA caused aberrant splicing and significant intron retention, which was negatively correlated with TAF1 expression. Remarkably, CRISPR/Cas9 excision of the SVA rescued the aberrant transcriptional signature and normalized expression of TAF1 in patient-derived NSCs.</p>

| phs001525 | dbGaP

A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci

Project description:Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci, but are not designed to capture all structural variations in the human genome. Using long-read sequencing data, we discovered widespread structural variation within SVA (Sine-VNTR-Alu) elements, a class of great-ape specific transposable elements with gene-regulatory roles, which represents a major source of structural variability in the human population. We highlight the presence of structurally variable SVAs (SV-SVAs) in neurological disease-associated loci, and further associate SV-SVAs to disease-associated SNPs and differential gene expression using luciferase assays and expression quantitative trait loci data. Finally, we genetically deleted SV-SVAs in the BIN1 and CD2AP Alzheimer-associated risk loci and in the BCKDK Parkinson disease-associated risk locus and assessed multiple aspects of their gene-regulatory influence in a human neuronal context. Together, this study reveals a novel layer of genetic variation in transposable elements that may contribute to identification of the structural variants that are the actual drivers of disease-associations of GWAS loci.

2022-01-17 | GSE167409 | GEO

Amplicon-seq of SVA methylation in human sperm

Project description:DNA methylation, repressive histone modifications, and PIWI-interacting RNA are essential for controlling retroelement silencing in the mammalian germ line. Dysregulation of retroelement silencing is associated with male sterility. Although DNA methylation mechanisms have been extensively studied in mouse germ cells, little progress has been made in humans. Here, we show that the Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are associated with DNA methylation of retroelements in human primordial germ cells (hPGCs), and hominoid-specific retroelement SINE-VNTR-Alus (SVA) is subjected to transcription-directed de novo DNA methylation during human spermatogenesis. Furthermore, we show that the degree of de novo DNA methylation in SVAs varies among human individuals, which confers a major inter-individual epigenetic variation in sperm. Collectively, our results provide potential molecular mechanisms of how retroelements are regulated during human male germ cells

2021-08-01 | GSE174562 | GEO

Genetic deletion of ZNF91 in human embryonic stem cells leads to ectopic activation of SVAs and collective upregulation of KRAB zinc finger gene clusters

Project description:Transposable element (TE) invasions have shaped vertebrate genomes over the course of evolution. They have contributed an extra layer of species-specific gene regulation by providing novel transcription factor binding sites. In humans, SVA elements are one of three still active TE families, and approximately 2800 SVA insertions exist in the human genome, half of which are human-specific. TEs are often silenced by KRAB zinc finger (KZNF) proteins recruiting co-repressor proteins that establish a repressive chromatin state. A number of KZNFs have been reported to bind SVAs, but their individual contribution to repressing SVAs and their roles in suppressing SVA-mediated gene-regulatory effects remains elusive. We analyzed the genome-wide binding profile for ZNF91 in human cells and found that ZNF91 interacts with the VNTR region of SVAs. Through CRISPR-Cas9 mediated deletion of ZNF91 in human embryonic stem cells we established that loss of ZNF91 results in increased transcriptional activity of SVAs. In contrast, SVA activation was not observed upon genetic deletion of the ZNF611 gene encoding another strong SVA-interactor. Epigenetic profiling confirmed the loss of SVA repression in the absence of ZNF91 and revealed that mainly evolutionary young SVAs gain gene activation-associated epigenetic modifications. Genes close to activated SVAs showed a mild upregulation, indicating SVAs adopt properties of cis-regulatory elements in the absence of repression. Intriguingly, genome-wide de-repression of SVAs elicited the communal upregulation of KZNFs that reside in KZNF clusters. This phenomenon may provide new insights into the potential mechanisms utilized by the host genome to sense and counteract TE invasions.

2021-01-28 | GSE162571 | GEO

The contribution of Alu exons to the human proteome

Project description:Alu element is a major contributor to lineage-specific new exons in the primate and human genomes. Recent studies indicate that some Alu exons have high transcript inclusion levels or tissue-specific splicing profiles, and may play important regulatory roles in modulating mRNA degradation or translational efficiency. However, the contribution of Alu exons to the human proteome remains unclear and controversial. The prevailing view is that exons derived from young repetitive elements (such as Alu) are restricted to regulatory functions but do not have adequate evolutionary time to be incorporated into stable, functional proteins. In this work, we adopt a proteotranscriptomics approach to systematically assess the contribution of Alu exons to the human proteome. Using RNA sequencing, ribosome profiling, and mass spectrometry data of diverse human tissues and cell lines, we provide evidence for the translational activities of Alu exons and the presence of Alu exon derived peptides in human proteins. These Alu exon peptides represent species-specific protein differences between primates and other mammals, and in certain instances even between humans and closely related nonhuman primates.Â In the RNA editing enzyme ADARB1, which contains an Alu exon peptide in its catalytic domain, RNA editing analyses of RNA-sequencing data demonstrate that both the Alu exon skipping and inclusion isoforms encode active RNA editing enzymes, while the Alu exon peptide may fine tune the editing activities of the ADARB1 protein productsÂ . Together, our data indicate that Alu elements have contributed to the acquisition of novel protein sequences during primate and human evolution. Comparing the A-I RNA editing levels during HEK293 (control), ADARB1 long isoform (with Alu exon) transfected, and short isoform (without Alu exon) transfected cells, each group has 3 replicates.

2015-12-10 | E-GEOD-65999 | biostudies-arrayexpress

Young transposable elements rewired gene regulatory networks in human and chimpanzee hippocampal intermediate progenitors

Project description:The hippocampus is associated with essential brain functions such as learning and memory. Human hippocampal volume is significantly greater than expected when compared to non-human apes, suggesting a recent expansion. Intermediate progenitors, which are able undergo multiple rounds of proliferative division before a final neurogenic division, may have played a role in the evolutionary hippocampal expansion. To investigate the evolution of gene regulatory networks underpinning hippocampal neurogenesis in apes, we leveraged the differentiation of human and chimpanzee induced Pluripotent Stem Cells into TBR2-positive hippocampal intermediate progenitors (hpIPCs). We find that the gene networks active in hpIPCs are significantly different between humans and chimpanzees, with ~2,500 genes differentially expressed. We demonstrate that species-specific transposon-derived enhancers contribute to these transcriptomic differences. Young transposons, predominantly Endogenous Retroviruses (ERV) and SINE-Vntr-Alus (SVA), were co-opted as enhancers in a species-specific manner. Human-specific SVAs provided substrates for thousands of novel TBR2 binding sites, and CRISPR-mediated repression of these SVAs attenuates the expression of ~25% of the genes that are upregulated in human intermediate progenitors relative to the same cell population in the chimpanzee

2021-11-24 | GSE189347 | GEO

Specific genomic features underlie the co-option of SVA transposons as cis-regulatory elements in the human genome

Project description:Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, why some TEs are co-opted as functional enhancers while others are not is underappreciated. SINE-Vntr-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-exclusive. Many studies indicated that the SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such process have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication into human stem-cell gene regulation. We found that ~750 SVAs are co-opted as functional cis-regulatory elements in human induced Pluripotent Stem Cells. Co-opted SVAs are significantly closer to genes and harbor more transcription factor binding sites than the not co-opted ones. We show that a long DNA-motif composed of flanking YY1/2 and OCT4 binding sites is enriched in the co-opted SVAs, and that these two factors bind, as predicted, near each other on the TE sequence. Repression of all the ~750 co-opted SVAs by CRISPRi in a line with stem-like properties (NCCIT) led to loss of YY1/OCT4 binding and alteration of neighboring gene expression. Ultimately, SVA repression resulted in ~3,000 differentially expressed genes, 131 of which were the nearest gene to an annotated SVA. In summary, we demonstrated that SVAs contribute significantly to human gene regulation, and that both genomic location and sequence composition contribute to SVA domestication in the gene regulatory networks.

2022-01-04 | GSE192951 | GEO

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