Epigenomic signatures reveal mechanistic clues and predictive markers for autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) comprises a heterogeneous group of neurodevelopmental outcomes in children with a commonality in deficits in social communication and language combined with repetitive behaviors and interests. The etiology of ASD is heterogeneous, as several hundred genes have been implicated as well as multiple in utero environmental exposures. Over the past two decades, epigenetic investigations, including DNA methylation, have emerged as a novel way to capture the complex interface of multivariate ASD etiologies. More recently, epigenome-wide association studies using human brain and surrogate accessible tissues have revealed some convergent genes that are epigenetically altered in ASD, many of which overlap with known genetic risk factors. Unlike transcriptomes, epigenomic signatures defined by DNA methylation from surrogate tissues such as placenta and cord blood can reflect past differences in fetal brain gene transcription, transcription factor binding, and chromatin. For example, the discovery of NHIP (neuronal hypoxia inducible, placenta associated) through an epigenome-wide association in placenta, identified a common genetic risk for ASD that was modified by prenatal vitamin use. While epigenomic signatures are distinct between different genetic syndromic causes of ASD, bivalent chromatin and some convergent gene pathways are consistently epigenetically altered in both syndromic and idiopathic ASD, as well as some environmental exposures. Together, these epigenomic signatures hold promising clues towards improved early prediction and prevention of ASD as well genes and gene pathways to target for pharmacological interventions. Future advancements in single cell and multi-omic technologies, machine learning, as well as non-invasive screening of epigenomic signatures during pregnancy or newborn periods are expected to continue to impact the translatability of the recent discoveries in epigenomics to precision public health.

Zmiz1 is a novel regulator of brain development associated with autism and intellectual disability

“…Our study reveals the presence of Zmiz1 in the axon-dendritic-somatic compartment, indicating novel functions of Zmiz1 beyond transcriptional regulation. In terms of gene regulation and chromatin remodeling, Zmiz1 function is mediated by activating histone modifications, adding complexity to the genetic network implicated in NDDs ( 7 , 56 , 57 ).…”

Axo-axonic synaptic input drives homeostatic plasticity by tuning the axon initial segment structurally and functionally

“…Although PL PNs have been implied in many behavioral paradigms, we chose to prioritize social behavior. This is because PL PNs has been consistently shown to have a negative impact on social behavior (51)(52)(53). Additionally, it is a behavioral paradigm that does not require extensive training, and thereby would not introduce other forms of plasticity that may interact or interfere the homeostatic plasticity we focused on.…”

Convergent Transcriptomic Evidence Reveals the Dysfunctional Quantitative Mechanism of Synaptic Plasticity Control in ASD

“…However, the integration of omics data, especially across RNA and protein realms at the cellular level in ASD, remains a challenge. Current studies primarily focus on genetic variations [2,[46][47][48][49][50][51], isolated gene expression discrepancies [52,53], and genetic loci or gene associations [54,55]. To address this issue and gain a more comprehensive understanding of ASD's molecular mechanisms, the concept of convergence related to a specific endophenotype has been introduced [56][57][58][59][60].…”