Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Playfoot, Christopher J; Duc, Julien; Sheppard, Shaoline; Dind, Sagane; Coudray, Alexandre; Planet, Evarist; Trono, Didier

doi:10.1101/2020.12.14.422620

Cited by 4 publications

(5 citation statements)

References 88 publications

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“…For any ORF start codon that overlapped a TE, we used a table of TE subfamily ages from Dfam to estimate the oldest possible lineage in which that TE may exist in the human genome. 32,61…”

Section: Transposable Element Insertion At Start Codonsmentioning

confidence: 99%

Developmental Dynamics of RNA Translation in the Human Brain

Duffy

Finander

Choi

et al. 2021

Preprint

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The precise regulation of gene expression is fundamental to neurodevelopment, plasticity, and cognitive function. While several studies have deeply profiled mRNA dynamics in the developing human brain, there is a fundamental gap in our understanding of accompanying translational regulation. We perform ribosome profiling from more than 70 human prenatal and adult cortex samples across ontogeny and into adulthood, mapping translation events at nucleotide resolution. In addition to characterizing the translational regulation of annotated open reading frames (ORFs), we identify thousands of previously unknown translation events, including small open reading frames (sORFs) that give rise to human- and/or brain-specific microproteins, many of which we independently verify using size-selected proteomics. Ribosome profiling in stem cell-derived human neuronal cultures further corroborates these findings and shows that several neuronal activity-induced long non-coding RNAs (lncRNAs), including LINC00473, a primate-specific lncRNA implicated in depression, encode previously undescribed microproteins. Physicochemical analysis of these brain microproteinss identifies a large class harboring arginine-glycine-glycine (RGG) repeats as strong candidates for regulating RNA metabolism. Moreover, we find that, collectively, these previously unknown human brain sORFs are enriched for variants associated with schizophrenia. In addition to significantly expanding the translational landscape of the developing brain, this atlas will serve as a rich resource for the annotation and functional interrogation of thousands of previously unknown brain-specific protein products.

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“…For any ORF start codon that overlapped a TE, we used a table of TE subfamily ages from Dfam to estimate the oldest possible lineage in which that TE may exist in the human genome. 32,61…”

Section: Transposable Element Insertion At Start Codonsmentioning

confidence: 99%

Developmental Dynamics of RNA Translation in the Human Brain

Duffy

Finander

Choi

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Recently, Playfoot and colleagues provided evidence for transposable element (TE) involvement in new ORF formation 32 . We directly explored this as a possible mechanism of sORF generation in the brain, finding that lncRNA-associated sORFs have an increased overlap with TE insertions compared to protein-coding ORFs (8% vs. 4%, respectively; Fig.…”

Section: Evolutionary Conservation Of Sorfsmentioning

confidence: 99%

“…For any ORF start codon that overlapped a TE, we used a table of TE subfamily ages from Dfam to estimate the oldest possible lineage in which that TE may exist in the human genome. 32,61…”

Section: Transposable Element Insertion At Start Codonsmentioning

confidence: 99%

Developmental dynamics of RNA translation in the human brain

et al. 2022

View full text Add to dashboard Cite

The precise regulation of gene expression is fundamental to neurodevelopment, plasticity, and cognitive function. While several studies have deeply profiled mRNA dynamics in the developing human brain, there is a fundamental gap in our understanding of accompanying translational regulation. We perform ribosome profiling from more than 70 human prenatal and adult cortex samples across ontogeny and into adulthood, mapping translation events at nucleotide resolution. In addition to characterizing the translational regulation of annotated open reading frames (ORFs), we identify thousands of previously unknown translation events, including small open reading frames (sORFs) that give rise to human-and/or brain-specific microproteins, many of which we independently verify using size-selected proteomics.Ribosome profiling in stem cell-derived human neuronal cultures further corroborates these findings and shows that several neuronal activity-induced long non-coding RNAs (lncRNAs), including LINC00473, a primate-specific lncRNA implicated in depression, encode previously undescribed microproteins. Physicochemical analysis of these brain microproteinss identifies a large class harboring arginine-glycine-glycine (RGG) repeats as strong candidates for regulating RNA metabolism. Moreover, we find that, collectively, these previously unknown human brain sORFs are enriched for variants associated with schizophrenia. In addition to significantly expanding the translational landscape of the developing brain, this atlas will serve as a rich resource for the annotation and functional interrogation of thousands of previously unknown brain-specific protein products. MAINThe human brain leverages extraordinary protein diversity to execute developmental programs, organize neural circuits, and perform complex cognitive tasks 1 . Proteomic diversity is

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“…Typically, TEs are most active in the germline but become silenced in adult tissues. However, the adult human brain represents an exception where TEs remain actively transcribed (Bodea et al 2018;Playfoot et al 2021). For example, some TE subfamilies are still active in human brains, including L1 (Suarez et al 2018), Alu elements (Larsen et al 2018) and SINE-VNTR-Alu elements (SVAs) (Hancks and Kazazian 2010).…”

Section: Graphical Abstract Introductionmentioning

confidence: 99%

“…Studying the expression of KRAB-ZNF genes and TEs in the evolution of the human brain has crucial relevance, since some TEs are actively transcribed in the development of the human brain (Bodea et al, 2018), including L1 subfamilies, and primate-specific Alu subfamilies (Hancks & Kazazian, 2010;Larsen et al, 2018). Furthermore, TE-derived promoters play a role in gene transcription within the human brain, which in turn suggests the significance of TEs in gene regulation during neurodevelopment (Playfoot et al, 2021). Interestingly, a substantial number of differentially expressed primate-specific KRAB-ZNF genes were detected in the adult prefrontal cortex, comparing humans to chimpanzees (Nowick et al, 2009) and newly evolved KRAB-ZNF genes were predominantly detected in the developing human brain (Zhang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Regulatory networks of KRAB zinc finger genes and transposable elements changed during human brain evolution and disease

Chen,

Maupas,

Nowick

2023

Preprint

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Transposable elements (TEs), with their ability to change positions within a genome, have paradoxically been seen as both a potentially deleterious genomic phenomenon and a potent driving force behind evolution. The genome-protecting KRAB zinc finger (KRAB-ZNF) proteins play a critical role in repressing TE expression within mammalian genomes, engaging in a dynamic interplay. This interplay was suggested to evolve according to an arms-race model, wherein TEs strive to transpose within the genome and KRAB-ZNFs adapt to suppress them. Despite indications of the involvement of TEs and KRAB-ZNFs in brain evolution and disease, a systematic analysis of their interactions is still lacking. In this study, we explored the functional connections between KRAB-ZNFs and TEs in the context of human brain evolution and Alzheimer’s disease (AD). We conducted an analysis of KRAB-ZNF genes and TEs expression patterns and networks using two independent RNA-seq datasets: (1) data from 33 human and multiple non-human primate brain regions, and (2) data from the temporal cortex and cerebellum of both healthy individuals and AD patients. To efficiently compare the regulatory networks across species, we developed the TEKRABber R package, which enables estimating TE and KRAB-ZNF expression levels and pairwise correlations between them, facilitating cross-species regulatory network comparisons. Our analysis highlighted species-specific expression variations, with many recently evolved TEs and KRAB-ZNF genes being differentially expressed between species, emphasizing their impact on evolution. Focusing on one-to-one negative correlations between TEs and KRAB-ZNF genes (negative TE:KRAB-ZNF), we found that many of those correlations engage recently evolved TEs and KRAB-ZNF genes and are specific to humans. Integrating findings from the second dataset, we identified 2492 human-specific negative TE:KRAB-ZNF pairs uniquely detectable in the healthy human temporal cortex, suggesting dysregulation in AD brains. A distinct subcluster in the network formed by these 2492 pairs consists of Alu elements, underscoring their unique role in human brain evolution and disease. Our results deepens insights into primate brain evolution and offer a new perspective on human neurodegenerative disease through the analysis of the negative TE:KRAB-ZNF regulatory network.Graphical Abstract

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Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Cited by 4 publications

References 88 publications

Developmental Dynamics of RNA Translation in the Human Brain

Developmental Dynamics of RNA Translation in the Human Brain

Developmental dynamics of RNA translation in the human brain

Regulatory networks of KRAB zinc finger genes and transposable elements changed during human brain evolution and disease

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