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We named these molecularly coordinated regions “variable chromatin modules” (VCMs), providing a conceptual framework of how regulatory variation might shape complex traits. To better understand the molecular mechanisms underlying VCM formation, here, we mechanistically dissect an uncharacterized VCM-modulating non-coding variant that is associated with reduced chronic lymphocytic leukemia (CLL) predisposition and disease progression. This common, germline variant constitutes a 5-bp indel that controls the activity of an AXIN2 gene-linked VCM by creating a MEF2 binding site, which, upon binding, activates a super-enhancer-like regulatory element. This triggers a change in TF binding activity and chromatin state at an enhancer cluster spanning >150 kb, coinciding with subtle, long-range chromatin compaction and robust AXIN2 up-regulation. Our results support a model in which the indel acts as an AXIN2 VCM-activating TF nucleation event, which modulates CLL pathology. Overall design: RNA-seq for the MEC1 CLL cell line with overexpression of AXIN2 or control using a lentiviral infection with the pLV-EF1a-IRES-Puro (#85132, Addgene) vector. ATAC-seq for crispred MEC1 cells to have both rs143348853 genotypes (homozygous ALT and REF). NGS Capture-C for the LCLs GM11931 and GM12282 using the rs143348853 locus as viewpoint."],"tag":["xref:PubMed:35440565"],"repository":["ENA"],"name_synonyms":["nuclear chromatin, leukemia, RNA polymerase II core promoter proximal region sequence-specific binding, cytoplasmic chromatin, T-cell leukemia, AGL4, zinc ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, homeobox 1, biosynthesis, Factor, SEPALLATA 2, metal ion regulated sequence-specific DNA binding RNA polymerase II transcription factor activity, Transcription Factor, Leukemias, transcription factor activity, zinc ion regulated core promoter proximal region sequence-specific DNA binding, RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity, leukaemia NOS, RNA polymerase II transcription factor activity, Leucocythaemia, sequence-specific distal enhancer binding RNA polymerase II transcription factor activity, leukaemia, metal ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, KNOTTED1-like homeobox gene 5, Chromatins, Leucocythaemias, multicellular organismal biosynthetic process, F14P3.4, Leucocythemia, single-organism biosynthetic process, Transcription, Factors, formation, anabolism, copper ion regulated core promoter proximal region sequence-specific binding., F14P3_4, F10N7_150, Leucocythemias, metal ion regulated core promoter proximal region sequence-specific binding, RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity, Transcription factor, F10N7.150, synthesis, RNA polymerase II proximal promoter sequence-specific DNA binding, copper ion regulated proximal promoter sequence-specific DNA binding, chromosome scaffold, copper ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, AGAMOUS-like 4, zinc ion regulated proximal promoter sequence-specific DNA binding, sequence-specific transcription regulatory region DNA binding RNA polymerase II transcription factor recruiting transcription factor activity, metal ion regulated sequence-specific DNA binding, metal ion regulated proximal promoter sequence-specific DNA binding, TRANSCRIPTION FACTOR, RNA polymerase II distal enhancer sequence-specific binding"],"description_synonyms":["nuclear chromatin, leukemia, RNA polymerase II core promoter proximal region sequence-specific binding, cytoplasmic chromatin, T-cell leukemia, AGL4, zinc ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, homeobox 1, biosynthesis, Factor, SEPALLATA 2, metal ion regulated sequence-specific DNA binding RNA polymerase II transcription factor activity, Transcription Factor, Leukemias, transcription factor activity, zinc ion regulated core promoter proximal region sequence-specific DNA binding, RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity, leukaemia NOS, RNA polymerase II transcription factor activity, Leucocythaemia, sequence-specific distal enhancer binding RNA polymerase II transcription factor activity, leukaemia, metal ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, KNOTTED1-like homeobox gene 5, Chromatins, Leucocythaemias, multicellular organismal biosynthetic process, F14P3.4, Leucocythemia, single-organism biosynthetic process, Transcription, Factors, formation, anabolism, copper ion regulated core promoter proximal region sequence-specific binding., F14P3_4, F10N7_150, Leucocythemias, metal ion regulated core promoter proximal region sequence-specific binding, RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity, Transcription factor, F10N7.150, synthesis, RNA polymerase II proximal promoter sequence-specific DNA binding, copper ion regulated proximal promoter sequence-specific DNA binding, chromosome scaffold, copper ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, AGAMOUS-like 4, zinc ion regulated proximal promoter sequence-specific DNA binding, sequence-specific transcription regulatory region DNA binding RNA polymerase II transcription factor recruiting transcription factor activity, metal ion regulated sequence-specific DNA binding, metal ion regulated proximal promoter sequence-specific DNA binding, TRANSCRIPTION FACTOR, RNA polymerase II distal enhancer sequence-specific binding"],"additional_accession":[]},"is_claimable":false,"name":"A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation","description":"A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation","dates":{"last_updated":"2025-09-24","first_public":"2022-02-11"},"accession":"PRJNA681797","cross_references":{"GEO":["GSE162387"],"taxon":["9606"],"PubMed":["35440565"]}}