{"doi":"10.1101/2022.09.12.507600","title":"Photoselective sequencing: microscopically-guided genomic measurements with subcellular resolution","abstract":"Abstract In biological systems, spatial organization is interconnected with genome function and regulation. However, methods that couple high-throughput genomic and epigenomic profiling with spatial information are lacking. Here, we developed Photoselective Sequencing, a spatially-informed DNA sequencing method to assay collections of cells or subcellular regions that share a unifying morphological trait. In Photoselective Sequencing, we prepare a blocked fragment library within a fixed biological specimen. Guided by fluorescence imaging, we remove the block in specific regions of interest using targeted illumination with near-UV light, ultimately allowing high-throughput sequencing of the selected fragments. To validate Photoselective Sequencing, we profile chromatin openness in fluorescently-labeled cell types within the mouse brain and demonstrate strong agreement with published single-cell ATAC-seq data. Using Photoselective Sequencing, we characterize the accessibility profiles of oligodendrocyte-lineage cells within the cortex and corpus-callosum regions of the brain. We develop a new computational strategy for decomposing bulk accessibility profiles by individual cell types, and report a relative enrichment of oligodendrocyte-progenitor-like cells in the cortex. Finally, we leverage Photoselective Sequencing for unbiased profiling of DNA at the nuclear periphery, a key chromatin organizing region. We compare and contrast the Photoselective Sequencing profile with lamin ChIP-seq data, and identify features beyond lamin interaction that are correlated with positioning at the nuclear periphery. These results collectively demonstrate that Photoselective Sequencing is a flexible and generalizable platform for exploring the interplay of spatial structures with genomic and epigenomic properties.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":304271,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":630639,"name":"Haiqi Chen","orcid":"0000-0001-7179-3229","position":1,"is_corresponding":false},{"id":7648,"name":"Andrew Earl","orcid":"0000-0002-5732-954X","position":2,"is_corresponding":false},{"id":997085,"name":"Julie A. Dobkin","orcid":"0009-0002-9233-4317","position":3,"is_corresponding":false},{"id":630641,"name":"Daniel Lesman","orcid":"0000-0002-9982-7344","position":4,"is_corresponding":false},{"id":3630,"name":"Jason D. Buenrostro","orcid":"0000-0001-9958-3987","position":5,"is_corresponding":false},{"id":24055,"name":"Fei Chen","orcid":"0000-0003-2308-3649","position":6,"is_corresponding":false},{"id":459939,"name":"Sarah Mangiameli","orcid":"0000-0002-6799-3436","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T00:32:32.651796Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}