Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains

Abstract

Genetic variants associated with autism spectrum disorders (ASDs) are enriched in genes encoding synaptic proteins and chromatin regulators. Although the role of synaptic proteins in ASDs is widely studied, the mechanism by which chromatin regulators contribute to ASD risk remains poorly understood. Upon profiling and analyzing the transcriptional and epigenomic features of genes expressed in the cortex, we uncovered a unique set of long genes that contain broad enhancer-like chromatin domains (BELDs) spanning across their entire gene bodies. Analyses of these BELD genes show that they are highly transcribed with frequent RNA polymerase II (Pol II) initiation and low Pol II pausing, and they exhibit frequent chromatin-chromatin interactions within their gene bodies. These BELD features are conserved from rodents to humans, are enriched in genes involved in synaptic function, and appear post-natally concomitant with synapse development. Importantly, we find that BELD genes are highly implicated in neurodevelopmental disorders, particularly ASDs, and that their expression is preferentially down-regulated in individuals with idiopathic autism. Finally, we find that the transcription of BELD genes is particularly sensitive to alternations in ASD-associated chromatin regulators. These findings suggest that the epigenomic regulation of BELD genes is important for post-natal cortical development and lend support to a model by which mutations in chromatin regulators causally contribute to ASDs by preferentially impairing BELD gene transcription.

FMRP activates the translation of large autism/intellectual disability proteins and stimulates N-end rule E3 ligase Poe/UBR4 production within puromycin-sensitive RNP particles

“…The median sum intron length of ASD/ID genes is 3.8-fold greater than that of all neuronally-expressed genes (78.3 kbps vs. 20.6 kbps, Fig. 1B), consistent with prior studies showing that ASD/ID genes tend to encode long genes (King et al 2013;Zhao et al 2018). (3) The untranslated regions of ASD/ID genes are slightly longer than average; the median 5'UTR length of ASD/ID genes is 1.6-fold longer than average (250 bps vs. 160 bps, Fig.…”

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

“…We show that the highest expression of Nrxn3, Rbfox1 and Nlgn1 coincides with the loss of chromatin contacts and unfolding of the entire domain, which we call 'TAD melting', reminiscent of the formation of chromatin puffs previously reported by microscopical assays 54 . Many long neuronal genes are regulated in a specialized manner, for example by the activity of topoisomerases 52 , by the presence of long stretches of broad H3K27ac and H3K4me1 which act as enhancer-like domains 58 , or through repressive mechanisms such as DNA methylation 59 . The regulation of these long neuronal genes is further complicated by intricate splicing dynamics 50,51 , which require highly dynamic and adaptive responses based on neuronal activation state.…”

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

“…Autism spectrum disorders (ASDs) are highly heritable, complex and pervasive conditions, characterized by communication deficits, restricted interests, emotional problems and cognitive impairments. Many genes traditionally thought to be involved in autism encode cell adhesion molecules and proteins involved in neurogenesis, synaptogenesis, synaptic functions and other cellular processes (Chen, Chang, & Huang, ; Guang et al, ; Zhao et al, ). In addition to the genetic component, a number of environmental factors participate in autism pathogenesis, affecting synapse activities, neuroimmune regulation, gastrointestinal function, metabolism and gene expression (Choi et al, ; Huang & Jin, ; MacFabe, ; Rizzetto, Fava, Tuohy, & Selmi, ).…”