Unraveling the three-dimensional (3D) genome architecture in Neurodevelopmental Disorders (NDDs).

The human genome, comprising millions of pairs of bases, serves as the blueprint of life, encoding instructions for cellular processes. However, genomes are not merely linear sequences; rather, the complex of DNA and histones, known as chromatin, exhibits complex organization across various levels, which profoundly influence gene expression and cellular function. Central to understanding genome organization is the emerging field of three-dimensional (3D) genome studies. Utilizing advanced techniques such as Hi-C, researchers have unveiled non-random dispositions of genomic elements, highlighting their importance in transcriptional regulation and disease mechanisms. Topologically Associating Domains (TADs), that demarcate regions of chromatin with preferential internal interactions, play crucial roles in gene regulation and are increasingly implicated in various diseases such as cancer and schizophrenia. However, their role in Neurodevelopmental Disorders (NDDs) remains poorly understood. Here, we focus on TADs and 3D conservation across the evolution and between cell types in NDDs. The investigation into genome organization and its impact on disease has led to significant breakthroughs in understanding NDDs etiology such ASD (Autism Spectrum Disorder). By elucidating the wide spectrum of ASD manifestations, researchers aim to uncover the underlying genetic and epigenetic factors contributing to its heterogeneity. Moreover, studies linking TAD disruption to NDDs underscore the importance of spatial genome organization in maintaining proper brain development and function. In summary, this review highlights the intricate interplay between genome organization, transcriptional control, and disease pathology, shedding light on fundamental biological processes and offering insights into the mechanisms underlying NDDs like ASD.