Journal Article

DKFZ-2026-00981

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png MLL4/KMT2D histone methyltransferase and JUNB cooperate in a feed-forward loop to support AP-1-dependent TGF-β signaling.

Chan, T. E. H.DKFZ* ; Islam, M. S.DKFZ* ; Fotouhi, O.DKFZ* ; Bozkurt, M.DKFZ* ; Nizamuddin, S.DKFZ* ; Schüle, K. M. ; Arnold, S. J. ; Timmers, H. T. M.DKFZ*

2026
HighWire Press Stanford, Calif.

Abstract: Transforming growth factor β (TGF-β) signaling is a highly pleiotropic pathway with an important role in development, homeostasis, and cancer. Chromatin regulators contribute to the regulation of TGF-β-responsive transcription. The requirement of subunits of the MLL3/MLL4 histone methyltransferase complexes for TGF-β responses has been reported. However, their exact roles are not fully understood. To investigate the functions of these complexes, we employed CRISPR/Cas9 genome editing to inactivate the KMT2C/MLL3 or KMT2D/MLL4 genes in human diploid epithelial cells. Time-course RNA-seq experiments revealed the requirement of MLL4 but not of MLL3 for TGF-β transcriptional responses. CUT&RUN experiments showed that MLL4 binding increases after TGF-β treatment and is especially enriched at AP-1 transcription factor binding sites. Interestingly, TGF-β-induced chromatin binding of MLL4 correlates with increases in H3K27ac but not in H3K4me1 modifications. Furthermore, TGF-β treatment sets off SMAD2-induced JUNB expression, which forms a feed-forward loop with MLL4. By inhibiting the activities of AP-1, the BAF chromatin remodeler, or the CBP/p300 histone acetyltransferase, we found that AP-1 binding and these chromatin regulators are all necessary for TGF-β induction of MLL4 binding and transcriptional activation of its genomic targets. Taken together, our study reveals distinctive roles for the MLL3 and MLL4 paralogs in the transcriptional response to TGF-β. In contrast to MLL3, MLL4 forms a feed-forward loop of JUNB, the BAF complex, and CBP/p300 to sustain transcription activation by TGF-β.

Keyword(s): AP-1 ; KMT2D/MLL4 ; TGF-β signaling ; chromatin ; transcription

Note: #DKTKZFB26# / 2026 Jul 1;40(13-14):1012-1028

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Freiburg (FR01)
2. DKTK FR Med. Epigenetik (FR02)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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