In primed human pluripotent stem cells (hPSCs) resembling post-implantation epiblast, numerous lineage-specific enhancers assume the poised chromatin state, co-marked by H3K4me1 and Polycomb-associate...

Background Neuropsychiatric disorders are highly complex conditions and the risk of developing a disorder has been tied to hundreds of genomic variants that alter the expression and/or RNA isoforms made by risk genes. However, how these genes contribute to disease risk and onset through altered expression and RNA splicing is not well understood. Results Combining our new bioinformatic pipeline IsoLamp with nanopore long-read amplicon sequencing, we deeply profile the RNA isoform repertoire of 31 high-confidence neuropsychiatric disorder risk genes in Human brain. We show most risk genes are more complex than previously reported, identifying 363 novel isoforms and 28 novel exons, including isoforms which alter protein domains, and genes such as ATG13 and GATAD2A where most expression was from previously undiscovered isoforms. The greatest isoform diversity is detected in the schizophrenia risk gene ITIH4. Mass spectrometry of brain protein isolates confirms translation of a novel exon skipping event in ITIH4, suggesting a new regulatory mechanism for this gene in the brain. Conclusions Our results emphasize the widespread presence of previously undetected RNA and protein isoforms in the human brain and provide an effective approach to address this knowledge gap. Uncovering the isoform repertoire of candidate neuropsychiatric risk genes will underpin future analyses of the functional impact these isoforms have on neuropsychiatric disorders, enabling the translation of genomic findings into a pathophysiological understanding of disease.

Multiscale proteomic network modeling of Alzheimer's disease integrates large-scale proteomic and genetic data from vulnerable brain regions and reveals key driver proteins such as AHNAK within a glia...

The authors discover a homeostatic process termed interstasis, in which an increased concentration of proteins within RNA–protein condensates induces the sequestration of their own mRNAs.

RNA sequencing in rare disease is conventionally used to resolve the effect of a variant on a single gene. Here, we apply a transcriptome-wide approach to detect disorders of the minor spliceosome. Th...

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DNA replication is molecularly asymmetric, due to distinct mechanisms for lagging and leading strand DNA synthesis. Whether chromatin assembly on newly replicated strands is also asymmetric remains un...

Genes are often activated by enhancers located at large genomic distances, and the importance of this positioning is poorly understood. By relocating promoter-reporter constructs into thousands of alt...

Nature Genetics - This Review discusses noncanonical DNA methylation (mCH) in animal genomes and highlights the remaining need to clarify whether mCH represents a conserved regulatory layer or a...

Sequencing analyses of human prefrontal cortex from donors ranging in age from 0.4 to 104 years show that ageing correlates with an accumulation of somatic mutations in short housekeeping genes and a reduction in the expression of these genes.

Epigenome editing programs gene silencing without inducing DNA breaks but challenges in delivery into human cells limit its broader use. Here, the authors present the RENDER platform, which uses virus...

Photoactivatable fluorescent proteins enable precise analysis of subcellular protein dynamics, but a comparable approach for photoactivated tagging subcellular RNA remains lacking. Here, we develop PA...