ArticleAmerican journal of human genetics2017
CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1 Expression via Thousands of Large, Programmed Genomic Deletions.
Article in American journal of human genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed, 155 citations in OpenAlex.
- Towards efficient perturbation for the noncoding genome.Nature communications · 2026Article
- Gigabase-scale deletion scanning of the human genome.bioRxiv : the preprint server for biology · 2026Article
- Functional interrogation of candidate cis-regulatory elements at the LDLR locus.PLoS genetics · 2026Article
- Review
- Mapping cis- and trans-regulatory target genes of human-specific deletions.Nature communications · 2025Article
- Transcriptional Regulation and Its Misregulation in Human Diseases: Recent Progress.International journal of molecular sciences · 2025Article
- Uncovering hidden enhancers through unbiased in vivo testing.Nature communications · 2025Article
- Engineering structural variants to interrogate genome function.Nature genetics · 2024Review
- DNA-binding factor footprints and enhancer RNAs identify functional non-coding genetic variants.Genome biology · 2024Article
- Epigenome editing technologies for discovery and medicine.Nature biotechnology · 2024Review
- Multicenter integrated analysis of noncoding CRISPRi screens.Nature methods · 2024Article
- Mapping the functional impact of non-coding regulatory elements in primary T cells through single-cell CRISPR screens.Genome biology · 2024Article
- Multiplexed screening reveals how cancer-specific alternative polyadenylation shapes tumor growth in vivo.Nature communications · 2024Article
- Parallelized engineering of mutational models using piggyBac transposon delivery of CRISPR libraries.Cell reports methods · 2024Article
- Combined CRISPRi and proteomics screening reveal a cohesin-CTCF-bound allele contributing to increased expression of RUVBL1 and prostate cancer progression.American journal of human genetics · 2023Article
- Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions.Nature genetics · 2023Article
- Evaluating the mouse neural precursor line, SN4741, as a suitable proxy for midbrain dopaminergic neurons.BMC genomics · 2023Article
- Article
- Deletion mapping of regulatory elements for GATA3 in T cells reveals a distal enhancer involved in allergic diseases.American journal of human genetics · 2023Article
- Translating non-coding genetic associations into a better understanding of immune-mediated disease.Disease models & mechanisms · 2023Review
33 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion ("ScanDel"). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder. Altogether, we programmed 4,342 overlapping 1 and 2 kb deletions that tiled 206 kb centered on HPRT1 (including 87 kb upstream and 79 kb downstream) with median 27-fold redundancy per base. We functionally assayed programmed deletions in parallel by selecting for loss of HPRT function with 6-thioguanine. As expected, sequencing gRNA pairs before and after selection confirmed that all HPRT1 exons are needed. However, HPRT1 function was robust to deletion of any intergenic or deeply intronic non-coding region, indicating that proximal regulatory sequences are sufficient for HPRT1 expression. Although our screen did identify the disruption of exon-proximal non-coding sequences (e.g., the promoter) as functionally consequential, long-read sequencing revealed that this signal was driven by rare, imprecise deletions that extended into exons. Our results suggest that no singular distal regulatory element is required for HPRT1 expression and that distal mutations are unlikely to contribute substantially to Lesch-Nyhan syndrome burden. Further application of ScanDel could shed light on the role of regulatory mutations in disease at other loci while also facilitating a deeper understanding of endogenous gene regulation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.