biostudies-literatureDavis ECouncil for Higher Education (CHE)Council for Higher EducationNeuroendocrine Tumor Research Foundation (NETRF)Neuroendocrine Tumor Research Foundatione2405001121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11474083biostudies-literatureUnknown121(41)Well-differentiated low-grade lung neuroendocrine tumors (lung carcinoids or LNETs) are histopathologically classified as typical and atypical LNETs, but each subtype is still heterogeneous at both the molecular level and its clinical manifestation. Here, we report genome-wide profiles of primary LNETs' cis-regulatory elements by H3K27ac ChIP-seq with matching RNA-seq profiles. Analysis of these regulatory landscapes revealed three regulatory subtypes, independent of the typical/atypical classification. We identified unique differentiation signals that delineate each subtype. The "proneuronal" subtype emerges under the influence of ASCL1, SOX4, and TCF4 transcription factors, embodying a pronounced proneuronal signature. The "luminal-like" subtype is characterized by gain of acetylation atProceedings of the National Academy of Sciences of the United States of AmericaEnhancer landscape of lung neuroendocrine tumors reveals regulatory and developmental signatures with potential theranostic implications.PMC11474083NABrim CIzhar UHecht MAntman IDrier YAbu Akar FAbu-Kamel SJumaa MWald OMaimon OTzur TAvniel-Polak SGrozinsky-Glasberg SDavis EMaron YAtlan KSaadoun TBel-Ange AfalseEnhancer landscape of lung neuroendocrine tumors reveals regulatory and developmental signatures with potential theranostic implications.Well-differentiated low-grade lung neuroendocrine tumors (lung carcinoids or LNETs) are histopathologically classified as typical and atypical LNETs, but each subtype is still heterogeneous at both the molecular level and its clinical manifestation. Here, we report genome-wide profiles of primary LNETs' cis-regulatory elements by H3K27ac ChIP-seq with matching RNA-seq profiles. Analysis of these regulatory landscapes revealed three regulatory subtypes, independent of the typical/atypical classification. We identified unique differentiation signals that delineate each subtype. The "proneuronal" subtype emerges under the influence of ASCL1, SOX4, and TCF4 transcription factors, embodying a pronounced proneuronal signature. The "luminal-like" subtype is characterized by gain of acetylation at2024-01-01T00:00:00Z2024 Oct2026-06-02T11:54:15.38Z2025-07-01T03:05:40.043ZS-EPMC114740833936164810.1073/pnas.2405001121