SET1/MLL complexes control transcription independently of H3K4me3

Au, H. Y. A.; Szczurek, A. T.; de Krijger, I.; Kjelstrup-Osorio, N.; Hughes, A. L.; Lastuvkova, A.; Vermeulen, M.; Klose, R. J.

doi:10.64898/2025.12.08.692985

bioRxiv · 10.64898/2025.12.08.692985

SET1/MLL complexes control transcription independently of H3K4me3

Au, H. Y. A.·Szczurek, A. T.·de Krijger, I.·Kjelstrup-Osorio, N.·Hughes, A. L.·Lastuvkova, A.·Vermeulen, M.·Klose, R. J.

View original source ↗Export metadata ↓

Abstract

Histone H3 lysine 4 trimethylation (H3K4me3) at gene promoters is thought to play a central role in gene transcription. H3K4 methylation is deposited by the SET1 (A/B) and MLL (1-4) multi-protein complexes, but discovering how these essential enzymes shape H3K4me3 has been extremely challenging due to their multiplicity. This has also made determining whether SET1/MLL complexes control transcription through H3K4me3, or non-catalytic activities, an impenetrable problem. Here, we overcome these challenges through leveraging genome-engineering and combinatorial SET1/MLL protein depletion, integrated with genomics, proteomics, and live-cell transcription imaging. We uncover a new SET1B complex and reveal that SET1 and MLL1/2 complexes synergise to define H3K4me3 at gene regulatory elements. Unexpectedly, by decoupling SET1/MLL complex occupancy at promoters from H3K4me3, we discover they primarily control transcription independently of H3K4me3 through counteracting promoter-proximal termination and supporting transcription burst size. These discoveries reveal a new H3K4me3-independent logic for SET1/MLL-dependent control of gene transcription.

Explore related subjects

genomics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Au, H. Y. A., Szczurek, A. T., de Krijger, I., Kjelstrup-Osorio, N., Hughes, A. L., Lastuvkova, A., Vermeulen, M., Klose, R. J.. 2025-12-10. SET1/MLL complexes control transcription independently of H3K4me3. https://doi.org/10.64898/2025.12.08.692985

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

A hydrogen-producing mitochondrion in an anaerobic eukaryotrophic rhizarian

Diverse eukaryotes thrive under low oxygen conditions, in part through highly modified mitochondrion-related organelles (MROs) that use alternate metabolic pathways to support ATP production and cofactor recycling. Anaerobic lifestyles have evolved repeatedly across the eukaryotic tree of life, each providing an independent opportunity to understand how eukaryotes adapt to life in low oxygen conditions. Here, we use single-cell transcriptomics to reconstruct the MRO metabolism of PCE SSF, a benthic eukaryotrophic flagellate and the first cultivated representative of Novel Clade 12 (NC12; Rhizaria), an independently anaerobic rhizarian lineage. PCE SSF possesses an anaerobic hydrogen-producing mitochondrion capable of hydrogenosome-type substrate-level phosphorylation. It also retains a nearly complete but likely branched tricarboxylic acid pathway that lacks citrate synthase and malate dehydrogenase. The function of citrate synthase may instead be fulfilled by the typically cytosolic ATP citrate lyase, previously reported in this context only in the anaerobic cercozoan, Brevimastigomonas motovehiculus. Unlike B. motovehiculus, however, PCE SSF retains only Complex II and the NuoE/NuoF subunits of the electron transport chain and lacks a mitochondrial genome. Together, these features indicate an atypical and reduced mitochondrial metabolism, highlighting the diversity of evolutionary solutions to anaerobic energy metabolism in eukaryotes.

genomics↗

bioRxiv2026

A single-nucleus multi-omic atlas of gene regulation across 21 adult human tissues

Diverse human cell types establish specialized functions through lineage- and context-specific regulatory programs. Interpreting non-coding genetic risk requires integrated multi-omic reference maps that directly connect regulatory DNA to cellular expression across human tissues. Here we present a single-nucleus multi-omic atlas comprising 459,856 transcriptomic and chromatin accessibility profiles from 21 adult human tissues and four donors, including paired measurements from 160,688 nuclei. The atlas resolves nine cell lineages, 61 broad cell types and 313 subclusters, and identifies 1,085,062 candidate cis-regulatory elements (cCREs), including 161,270 novel elements absent from ENCODE. Regulatory activity was dominated by cell identity but refined by tissue context. Joint profiling enabled 871,177 cCRE-gene associations and revealed lineage-specific regulatory architectures. Cross-tissue accessibility further identified lineage-restricted and constitutively inaccessible chromatin domains, the latter showing preferential hypomethylation across human cancers. Furthermore, we leverage this dataset to train sequence-to-function models to predict chromatin-accessibility effects for 548,656 fine-mapped variants, identifying 18,133 high-effect variants, including 1,120 broadly active variants. Models trained for eight endothelial subtypes further resolve predicted variant effects across vascular beds. Together, this atlas provides a comprehensive cellular and computational framework for interpreting regulatory sequence, context-dependent gene control, and complex trait genetics across the human body.

genomics↗

bioRxiv2026

The chromosome level genome of the Blueberry Stem Gall Wasp, Hemadas nubilipennis (Hymenoptera: Ormyridae) on lowbush blueberry (Vaccinium angustifolium) reveals repeat-driven expansion

Gall-inducing wasps are emerging models for studying plantinsect coevolution, host manipulation, host plant adaptation, and speciation, yet chromosome-level resources remain scarce for most lineages. The blueberry stem gall wasp (BSGW), Hemadas nubilipennis (Hymenoptera: Ormyridae), is native to North America where it induces galls on both lowbush (Vaccinium angustifolium) and highbush blueberries (V. corymbosum). Recently, BSGW has reached outbreak densities in cultivated highbush production. Given that (a) the biology has been characterized primarily from natural lowbush-associated populations, (b) the absence of genomic resources limits comparative analyses, and (c) populations on cultivated highbush represent a recent host shift, we generated the first chromosome-level genome from wild lowbush blueberry. The BSGW genome consists of five chromosome-scale scaffolds totaling 1.08 Gb (N50 = 218 Mb), the second largest known in Chalcidoidea. Comparative analysis reveals that genome size variation is driven primarily by transposable element proliferation (R = 0.96, p < 0.001), with BSGW exhibiting a high proportion of unclassified TEs. Gene-body methylation is conserved, enriched in exons of broadly expressed core genes, and correlates with gene density. The mitochondrial genome (18,697 bp) exhibits extensive gene rearrangement, and COI sequences reveal 4.35.4% divergence from geographically distant populations, suggesting a complex of cryptic species. Additionally, we assemble a near-complete genome of the endosymbiont Wolbachia pipientis (Supergroup A), which encodes PifA and PifB effectors potentially linked to parthenogenesis. These resources establish a foundation for population genomics, taxonomic revision, and applied management, while providing insights into genome architecture, epigenetics, and symbiont interactions.

genomics↗