Biology subjects

Apontes, P.

Publications and source records attributed to Apontes, P..

4 recordsLinked to original sources

bioRxiv2021

Transcribed enhancers in the human brain identify novel disease risk mechanisms

Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding the population-level variation of enhancers in the human brain. Besides regulating tissue- and cell-type-specific transcription of target genes, enhancers themselves can be transcribed. We expanded the catalog of known human brain transcribed enhancers by an order of magnitude by generating and jointly analyzing large-scale cell-type-specific transcriptome and regulome data. Examination of the transcriptome in 1,382 brain samples in two independent cohorts identified robust expression of transcribed enhancers. We explored gene-enhancer coordination and found that enhancer-linked genes are strongly implicated in neuropsychiatric disease. We identified significant expression quantitative trait loci (eQTL) for 25,958 enhancers which mediate 6.8% of schizophrenia heritability, mostly independent from standard gene eQTL. Inclusion of enhancer eQTL in transcriptome-wide association studies enhanced functional interpretation of disease loci. Overall, our study characterizes the enhancer-gene regulome and genetic mechanisms in the human cortex in both healthy and disease states.

neuroscience↗

bioRxiv2021

The three-dimensional landscape of chromatin accessibility in Alzheimer's disease

Much is still unknown about the neurobiology of Alzheimers disease (AD). To better understand AD, we generated 636 ATAC-seq libraries from cases and controls to construct detailed genomewide chromatin accessibility maps of neurons and non-neurons from two AD-affected brain regions, the entorhinal cortex and superior temporal gyrus. By analyzing a total of 19.6 billion read pairs, we expanded the known repertoire of regulatory sequences in the human brain. Multi-omic data integration associated global patterns of chromatin accessibility with gene expression and identified cell-specific enhancer-promoter interactions. Using inter-individual variation in chromatin accessibility, we define cis-regulatory domains capturing the 3D structure of the genome. Multifaceted analyses uncovered disease associated perturbations impacting chromatin accessibility, transcription factor regulatory networks and the 3D genome, and implicated transcriptional dysregulation in AD. Overall, we applied a systematic approach to understand the role of the 3D genome in AD and to illuminate novel disease biology that can advance diagnosis and therapy.

neuroscience↗

bioRxiv2020

Evolution of regulatory signatures in primate cortical neurons at cell type resolution

The human cerebral cortex contains many cell types that likely underwent independent functional changes during evolution. However, cell type-specific regulatory landscapes in the cortex remain largely unexplored. Here we report epigenomic and transcriptomic analyses of the two main cortical neuronal subtypes, glutamatergic projection neurons and GABAergic interneurons, in human, chimpanzee and rhesus macaque. Using genome-wide profiling of the H3K27ac histone modification, we identify neuron-subtype-specific regulatory elements that previously went undetected in bulk brain tissue samples. Human-specific regulatory changes are uncovered in multiple genes, including those associated with language, autism spectrum disorder and drug addiction. We observe preferential evolutionary divergence in neuron-subtype-specific regulatory elements and show that a substantial fraction of pan-neuronal regulatory elements undergo subtype-specific evolutionary changes. This study sheds light on the interplay between regulatory evolution and cell-type-dependent gene expression programs, and provides a resource for further exploration of human brain evolution and function. SIGNIFICANCEThe cerebral cortex of the human brain is a highly complex, heterogeneous tissue that contains many cell types which are exquisitely regulated at the level of gene expression by non-coding regulatory elements, presumably, in a cell-type-dependent manner. However, assessing the regulatory elements in individual cell types is technically challenging, and therefore, most of the previous studies on gene regulation were performed with bulk brain tissue. Here we analyze two major types of neurons isolated from the cerebral cortex of humans, chimpanzees and rhesus macaques, and report complex patterns of cell-type-specific evolution of the regulatory elements in numerous genes. Many genes with evolving regulation are implicated in language abilities as well as psychiatric disorders.

evolutionary biology↗

bioRxiv2020

Transcriptional and epigenetic characterization of early striosomes identifies Foxf2 and Olig2 as factors required for development of striatal compartmentation and neuronal phenotypic differentiation

The basal ganglia, best known for processing information required for multiple aspects of movement, is also part of a network which regulates reward and cognition. The major output nucleus of the basal ganglia is the striatum, and its functions are dependent on neuronal compartmentation, including striosomes and matrix, which are selectively affected in disease. Striatal projection neurons are GABAergic medium spiny neurons (MSNs), all of which share basic molecular signatures but are subtyped by selective expression of receptors, neuropeptides, and other gene families. Neurogenesis of the striosome and matrix occurs in separate waves, but the factors regulating terminal neuronal differentiation following migration are largely unidentified. We performed RNA- and ATAC-seq on sorted murine striosome and matrix cells at postnatal day 3. Focusing on the striosomal compartment, we validated the localization and role of transcription factors and their regulator(s), previously not known to be associated with striatal development, including Irx1, Foxf2, Olig2 and Stat1/2. In addition, we validated the enhancer function of a striosome-specific open chromatin region located 15Kb downstream of the Olig2 gene. These data and data bases provide novel tools to dissect and manipulate the networks regulating MSN compartmentation and differentiation and thus provide new approaches to establishing MSN subtypes from human iPSCs for disease modeling and drug discovery.

neuroscience↗