Biology subjects

Casella, A. M.

Publications and source records attributed to Casella, A. M..

4 recordsLinked to original sources

bioRxiv2021

Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the prenatal human hypothalamus

The development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. We sequenced the transcriptomes of 40,927 cells from the prenatal human hypothalamus spanning from 6 to 25 gestational weeks and 25,424 mature neurons in regions of the adult human hypothalamus, revealing a temporal trajectory from proliferative stem cell populations to mature neurons and glia. Developing hypothalamic neurons followed branching trajectories leading to 170 transcriptionally distinct neuronal subtypes in ten hypothalamic nuclei in the adult. The uniqueness of hypothalamic neuronal lineages was examined developmentally by comparing excitatory lineages present in cortex and inhibitory lineages in ganglionic eminence from the same individuals, revealing both distinct and shared drivers of neuronal maturation across the human forebrain. Cross-species comparisons to the mouse hypothalamus identified human-specific POMC populations expressing unique combinations of transcription factors and neuropeptides. These results provide the first comprehensive transcriptomic view of human hypothalamus development at cellular resolution. One-Sentence SummaryUsing single-cell genomics, we reconstructed the developmental lineages by which precursor populations give rise to 170 distinct neuronal subtypes in the human hypothalamus.

neuroscience↗

bioRxiv2021

Regulome-wide association study identifies enhancer properties associated with risk for schizophrenia

Genetic risk for complex traits is strongly enriched in non-coding genomic regions involved in gene regulation, especially enhancers. However, we lack adequate tools to connect the characteristics of these disruptions to genetic risk. Here, we propose RWAS (Regulome Wide Association Study), a new framework to identify the characteristics of enhancers that contribute to genetic risk for disease. Applying our technique to interrogate genetic risk for schizophrenia, we found that risk-associated enhancers in this disease are predominantly active in the brain, evolutionarily conserved, and AT-rich. The association between AT percentage and risk corresponds to an overrepresentation in risk-associated enhancers for the binding sites of transcription factors that recognize AT-rich cis-regulatory motifs. Several of the TFs identified in our model as being overrepresented in risk-associated enhancers, including MEF2C, are master regulators of neuronal development. The genes that encode several of these TFs are themselves located at genetic risk loci for schizophrenia. This list also includes brain-expressed TFs that have not previously been linked to schizophrenia. In summary, we developed a generalizable approach that integrates GWAS summary statistics with enhancer characteristics to identify risk factors in tissue-specific regulatory regions. AUTHOR SUMMARYEnhancers are regulatory regions that influence gene expression via the binding of transcription factors. Risk for many heritable diseases is enriched in regulatory regions, including enhancers. In this study, we introduce a novel method of testing for association between enhancer attributes and risk and use this method to determine the enhancer characteristics that are associated with risk for schizophrenia. We found that enhancers associated with schizophrenia risk are both evolutionarily conserved and in physical contact with mutation-intolerant genes, many of which have neurodevelopmental functions. Risk-associated enhancers are also AT-rich and contain binding sites for neurodevelopmental transcription factors.

genomics↗

bioRxiv2019

Single cell epigenomic atlas of the developing human brain and organoids

Dynamic changes in chromatin accessibility coincide with important aspects of neuronal differentiation, such as fate specification and arealization and confer cell type-specific associations to neurodevelopmental disorders. However, studies of the epigenomic landscape of the developing human brain have yet to be performed at single-cell resolution. Here, we profiled chromatin accessibility of >75,000 cells from eight distinct areas of developing human forebrain using single cell ATAC-seq (scATACseq). We identified thousands of loci that undergo extensive cell type-specific changes in accessibility during corticogenesis. Chromatin state profiling also reveals novel distinctions between neural progenitor cells from different cortical areas not seen in transcriptomic profiles and suggests a role for retinoic acid signaling in cortical arealization. Comparison of the cell type-specific chromatin landscape of cerebral organoids to primary developing cortex found that organoids establish broad cell type-specific enhancer accessibility patterns similar to the developing cortex, but lack many putative regulatory elements identified in homologous primary cell types. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.

developmental biology↗

bioRxiv2019

Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty

Age-related hearing impairment (ARHI), one of the most common medical conditions, is strongly heritable, yet its genetic causes remain largely unknown. We conducted a meta-analysis of GWAS summary statistics from multiple hearing-related traits in the UK Biobank (n = up to 323,978) and identified 31 genome-wide significant risk loci for self-reported hearing difficulty (p < 5e-8), of which 30 have not been reported previously in the peer-reviewed literature at genome-wide significance. We investigated the regulatory and cell specific expression for these loci by generating mRNA-seq, ATAC-seq, and single-cell RNA-seq from cells in the mouse cochlea. Risk-associated genes were most strongly enriched for expression in cochlear epithelial cells, as well as for genes related to sensory perception and known Mendelian deafness genes, supporting their relevance to auditory function. Regions of the human genome homologous to open chromatin in sensory epithelial cells from the mouse were strongly enriched for heritable risk for hearing difficulty, even after adjusting for baseline effects of evolutionary conservation and cell-type nonspecific regulatory regions. Epigenomic and statistical fine-mapping most strongly supported 50 putative risk genes. Of these, at least 39 were expressed robustly in mouse cochlea and 16 were enriched specifically in sensory hair cells. These results reveal new risk loci and risk genes for hearing difficulty and suggest an important role for altered gene regulation in the cochlear sensory epithelium.

genetics↗