{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:28:12Z","timestamp":1780100892620,"version":"3.54.0"},"reference-count":47,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T00:00:00Z","timestamp":1672963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ERANET-NEURON","award":["Brain4sight"],"award-info":[{"award-number":["Brain4sight"]}]},{"name":"ERANET-NEURON","award":["GJC21176"],"award-info":[{"award-number":["GJC21176"]}]},{"name":"Fondazione Telethon-Fondazione Cariplo Alliance","award":["Brain4sight"],"award-info":[{"award-number":["Brain4sight"]}]},{"name":"Fondazione Telethon-Fondazione Cariplo Alliance","award":["GJC21176"],"award-info":[{"award-number":["GJC21176"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>DNA sequence variants (single nucleotide polymorphisms or variants, SNPs\/SNVs; copy number variants, CNVs) associated to neurodevelopmental disorders (NDD) and traits often map on putative transcriptional regulatory elements, including, in particular, enhancers. However, the genes controlled by these enhancers remain poorly defined. Traditionally, the activity of a given enhancer, and the effect of its possible alteration associated to the sequence variants, has been thought to influence the nearest gene promoter. However, the obtainment of genome-wide long-range interaction maps in neural cells chromatin challenged this view, showing that a given enhancer is very frequently not connected to the nearest promoter, but to a more distant one, skipping genes in between. In this Perspective, we review some recent papers, who generated long-range interaction maps (by HiC, RNApolII ChIA-PET, Capture-HiC, or PLACseq), and overlapped the identified long-range interacting DNA segments with DNA sequence variants associated to NDD (such as schizophrenia, bipolar disorder and autism) and traits (intelligence). This strategy allowed to attribute the function of enhancers, hosting the NDD-related sequence variants, to a connected gene promoter lying far away on the linear chromosome map. Some of these enhancer-connected genes had indeed been already identified as contributive to the diseases, by the identification of mutations within the gene\u2019s protein-coding regions (exons), validating the approach. Significantly, however, the connected genes also include many genes that were not previously found mutated in their exons, pointing to novel candidate contributors to NDD and traits. Thus, long-range interaction maps, in combination with DNA variants detected in association with NDD, can be used as \u201cpointers\u201d to identify novel candidate disease-relevant genes. Functional manipulation of the long-range interaction network involving enhancers and promoters by CRISPR-Cas9-based approaches is beginning to probe for the functional significance of the identified interactions, and the enhancers and the genes involved, improving our understanding of neural development and its pathology.<\/jats:p>","DOI":"10.3390\/ijms24021164","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T02:09:39Z","timestamp":1673230179000},"page":"1164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hooked Up from a Distance: Charting Genome-Wide Long-Range Interaction Maps in Neural Cells Chromatin to Identify Novel Candidate Genes for Neurodevelopmental Disorders"],"prefix":"10.3390","volume":"24","author":[{"given":"Sara","family":"Mercurio","sequence":"first","affiliation":[{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca, piazza della Scienza 2, 20126 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Pozzolini","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca, piazza della Scienza 2, 20126 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Baldi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca, piazza della Scienza 2, 20126 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Baril\u00e0","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca, piazza della Scienza 2, 20126 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Pitasi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca, piazza della Scienza 2, 20126 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orazio","family":"Catona","sequence":"additional","affiliation":[{"name":"Institute of Informatics and Telematics (IIT), National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"D\u2019Aurizio","sequence":"additional","affiliation":[{"name":"Institute of Informatics and Telematics (IIT), National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0378-3808","authenticated-orcid":false,"given":"Silvia K.","family":"Nicolis","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca, piazza della Scienza 2, 20126 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/s41576-019-0209-0","article-title":"Towards a comprehensive catalogue of validated and target-linked human enhancers","volume":"21","author":"Gasperini","year":"2020","journal-title":"Nat. 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