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Transposons contribute to the acquisition of cell type-specific cis-elements in the brain.

ABSTRACT: Mammalian brains have evolved in stages over a long history to acquire higher functions. Recently, several transposable element (TE) families have been shown to evolve into cis-regulatory elements of brain-specific genes. However, it is not fully understood how TEs are important for gene regulatory networks. Here, we performed a single-cell level analysis using public data of scATAC-seq to discover TE-derived cis-elements that are important for specific cell types. Our results suggest that DNA elements derived from TEs, MER130 and MamRep434, can function as transcription factor-binding sites based on their internal motifs for Neurod2 and Lhx2, respectively, especially in glutamatergic neuronal progenitors. Furthermore, MER130- and MamRep434-derived cis-elements were amplified in the ancestors of Amniota and Eutheria, respectively. These results suggest that the acquisition of cis-elements with TEs occurred in different stages during evolution and may contribute to the acquisition of different functions or morphologies in the brain.

SUBMITTER: Sekine K

PROVIDER: S-EPMC10257727 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Transposons contribute to the acquisition of cell type-specific cis-elements in the brain.

Sekine Kotaro K Onoguchi Masahiro M Hamada Michiaki M

Communications biology 20230610 1

Mammalian brains have evolved in stages over a long history to acquire higher functions. Recently, several transposable element (TE) families have been shown to evolve into cis-regulatory elements of brain-specific genes. However, it is not fully understood how TEs are important for gene regulatory networks. Here, we performed a single-cell level analysis using public data of scATAC-seq to discover TE-derived cis-elements that are important for specific cell types. Our results suggest that DNA e ...[more]

PMID: 37301950

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Project description:Recent large genome-wide association studies have identified multiple confident risk loci linked to addiction-associated behavioral traits. Most genetic variants linked to addiction-associated traits lie in noncoding regions of the genome, likely disrupting cis-regulatory element (CRE) function. CREs tend to be highly cell type-specific and may contribute to the functional development of the neural circuits underlying addiction. Yet, a systematic approach for predicting the impact of risk variants on the CREs of specific cell populations is lacking. To dissect the cell types and brain regions underlying addiction-associated traits, we applied stratified linkage disequilibrium score regression to compare genome-wide association studies to genomic regions collected from human and mouse assays for open chromatin, which is associated with CRE activity. We found enrichment of addiction-associated variants in putative CREs marked by open chromatin in neuronal (NeuN+) nuclei collected from multiple prefrontal cortical areas and striatal regions known to play major roles in reward and addiction. To further dissect the cell type-specific basis of addiction-associated traits, we also identified enrichments in human orthologs of open chromatin regions of female and male mouse neuronal subtypes: cortical excitatory, D1, D2, and PV. Last, we developed machine learning models to predict mouse cell type-specific open chromatin, enabling us to further categorize human NeuN+ open chromatin regions into cortical excitatory or striatal D1 and D2 neurons and predict the functional impact of addiction-associated genetic variants. Our results suggest that different neuronal subtypes within the reward system play distinct roles in the variety of traits that contribute to addiction.SIGNIFICANCE STATEMENT We combine statistical genetic and machine learning techniques to find that the predisposition to for nicotine, alcohol, and cannabis use behaviors can be partially explained by genetic variants in conserved regulatory elements within specific brain regions and neuronal subtypes of the reward system. Our computational framework can flexibly integrate open chromatin data across species to screen for putative causal variants in a cell type- and tissue-specific manner for numerous complex traits.

Project description:BackgroundCell specific gene expression is largely regulated by different combinations of transcription factors that bind cis-elements in the upstream promoter sequence. However, experimental detection of cis-elements is difficult, expensive, and time-consuming. This provides a motivation for developing bioinformatic methods to identify cis-elements that could prioritize future experimental studies. Here, we use motif discovery algorithms to predict transcription factor binding sites involved in regulating the differences between murine rod and cone photoreceptor populations.ResultsTo identify highly conserved motifs enriched in promoters that drive expression in either rod or cone photoreceptors, we assembled a set of murine rod-specific, cone-specific, and non-photoreceptor background promoter sequences. These sets were used as input to a newly devised motif discovery algorithm called Iterative Alignment/Modular Motif Selection (IAMMS). Using IAMMS, we predicted 34 motifs that may contribute to rod-specific (19 motifs) or cone-specific (15 motifs) expression patterns. Of these, 16 rod- and 12 cone-specific motifs were found in clusters near the transcription start site. New findings include the observation that cone promoters tend to contain TATA boxes, while rod promoters tend to be TATA-less (exempting Rho and Cnga1). Additionally, we identify putative sites for IL-6 effectors (in rods) and RXR family members (in cones) that can explain experimental data showing changes to cell-fate by activating these signaling pathways during rod/cone development. Two of the predicted motifs (NRE and ROP2) have been confirmed experimentally to be involved in cell-specific expression patterns. We provide a full database of predictions as additional data that may contain further valuable information. IAMMS predictions are compared with existing motif discovery algorithms, DME and BioProspector. We find that over 60% of IAMMS predictions are confirmed by at least one other motif discovery algorithm.ConclusionWe predict novel, putative cis-elements enriched in the promoter of rod-specific or cone-specific genes. These are candidate binding sites for transcription factors involved in maintaining functional differences between rod and cone photoreceptor populations.

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Transposons contribute to the acquisition of cell type-specific cis-elements in the brain.

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Transposons contribute to the acquisition of cell type-specific cis-elements in the brain.

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