Biology subjects

Lassen, F. H.

Publications and source records attributed to Lassen, F. H..

5 recordsLinked to original sources

bioRxiv2026

Menin maintains enhancer-promoter interactions in a leukemia-specific manner

Inhibition of the protein-protein interaction between Mixed Lineage Leukemia (MLL) and Menin is a promising therapy for both high-risk MLL-rearranged and NPM1-mutant (NPM1c) acute leukemias, yet the mechanistic basis of this dependency in distinct contexts remains unclear. By comparing the transcriptional responses of MLL::AF4 and NPM1c leukemia models to Menin inhibition, we find broad, acute transcriptional dysregulation in MLL::AF4 cells, but minor transcriptional consequences in NPM1c cells, despite similarities in Menin promoter occupancy. Using high-resolution Micro Capture-C, we discover that Menin drives enhancer activity and maintains enhancer-promoter contacts in MLL::AF4 cells but not in NPM1c cells. Crucially, Menin is also essential for patient-specific enhancer function in primary MLL-rearranged leukemia samples. Proteomic analysis further demonstrates that Menin associates with distinct transcriptional and elongation complexes in MLL::AF4 compared to NPM1c cells, supporting a context-dependent mechanism of action. Together, these findings establish that Menin is not a uniform transcriptional cofactor, but a context-dependent regulator of enhancer connectivity, and identifies enhancer-promoter architecture as a selective vulnerability in MLL-rearranged leukemia.

cancer biology↗

bioRxiv2025

Disruption of Cell-Type-Specific Molecular Programs of Medium Spiny Neurons in Autism

Autism spectrum disorders (ASD) are highly heritable neurodevelopmental conditions with major contributions from rare genetic variants. Most studies have focused on cortical mechanisms; even growing evidence implicates subcortical circuits in ASD etiology. To systematically map developmental and molecular alterations beyond the cortex, we profiled lineage relationships across five brain regions in an ASD mouse model. Most prominent changes emerged in the striatum, a hub for learning and motor control. Furthermore, we performed single-nucleus multiomic profiling of human putamen from ASD and neurotypical donors revealed cell-type-specific transcriptomic and regulatory alterations. Differential expression converged on synaptic and energy metabolic dysfunctions in D1 striosome medium spiny neurons (MSNs), coupled with astrocytic remodeling of synaptic support. Gene regulatory network analysis identified EGR3 and EGR1 as key transcriptional regulators of ASD-associated programs of D1 MSNs. Together, these results establish the striatum as a central node of ASD convergence and provide a multiomic resource for dissecting its subcortical mechanisms.

neuroscience↗

bioRxiv2023

Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3 mediated IL-1β production in human macrophages and microglia

Activation of the NACHT, LRR family pyrin domain containing 3 (NLRP3) inflammasome complex is an essential innate immune signalling mechanism. To reveal how human NLRP3 inflammasome assembly and activation are controlled, in particular by components of the ubiquitin system, proximity labelling, affinity purification and RNAi screening approaches were performed. Our study provides an intricate time-resolved molecular map of different phases of NLRP3 inflammasome activation. Also, we show that ubiquitin C-terminal hydrolase 1 (UCH-L1) interacts with the NACHT domain of NLRP3. Downregulation of UCH-L1 decreases pro-IL-1{beta} levels. UCH-L1 chemical inhibition with small molecules interfered with NLRP3 puncta formation and ASC oligomerization, leading to altered IL-1{beta} cleavage and secretion, particularly in microglia cells, which exhibited elevated UCH-L1 expression as compared to monocytes/macrophages. Altogether, we profiled NLRP3 inflammasome activation dynamics and highlight UCH-L1 as an important modulator of NLRP3-mediated IL-1{beta} production, suggesting that a pharmacological inhibitor of UCH-L1 may decrease inflammation-associated pathologies.

biochemistry↗

bioRxiv2023

Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes

BackgroundUntranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but little is known about the reasons for this variation in humans. Here, we set out to determine whether this variation, specifically in 5UTRs, correlates with gene dosage sensitivity. ResultsWe investigated 5UTR length, the number of alternative transcription start sites, the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5UTRs to form secondary structures. We explored how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. We show that LOEUF correlates with 5UTR length and complexity. Genes that are most intolerant to LoF have longer 5UTRs (P<1x10-15), greater TSS diversity (P<1x 10-15), and more upstream regulatory elements than their LoF tolerant counterparts. We show that these differences are evident in disease gene-sets, but not in recessive developmental disorder genes where LoF of a single allele is tolerated. ConclusionsOur results confirm the importance of post-transcriptional regulation through 5UTRs in tight regulation of mRNA and protein levels, particularly for genes where changes in dosage are deleterious and lead to disease. Finally, to support gene-based investigation we release a web-based browser tool, VuTR (https://vutr.rarediseasegenomics.org/), that supports exploration of the composition of individual 5UTRs and the impact of genetic variation within them.

genomics↗

bioRxiv2020

Genoppi: an open-source software for robust and standardized integration of proteomic and genetic data

Combining genetic and cell-type-specific proteomic datasets can lead to new biological insights and therapeutic hypotheses, but a technical and statistical framework for such analyses is lacking. Here, we present an open-source computational tool called Genoppi that enables robust, standardized, and intuitive integration of quantitative proteomic results with genetic data. We used Genoppi to analyze sixteen cell-type-specific protein interaction datasets of four proteins (TDP-43, MDM2, PTEN, and BCL2) involved in cancer and neurological disease. Through systematic quality control of the data and integration with published protein interactions, we show a general pattern of both cell-type-independent and cell-type-specific interactions across three cancer and one human iPSC-derived neuronal type. Furthermore, through the integration of proteomic and genetic datasets in Genoppi, our results suggest that the neuron-specific interactions of these proteins are mediating their genetic involvement in neurodevelopmental and neurodegenerative diseases. Importantly, our analyses indicate that human iPSC-derived neurons are a relevant model system for studying the involvement of TDP-43 and BCL2 in amyotrophic lateral sclerosis.

genetics↗