Biology subjects

Lautert-Dutra, W.

Publications and source records attributed to Lautert-Dutra, W..

4 recordsLinked to original sources

bioRxiv2026

DNMT1-Mediated Epigenetic Reprogramming Drives KMT2A Amplifications and Rearrangements

MLL/KMT2A amplifications and rearrangements are prevalent in infant, adult, and therapy-induced leukemia; however, the molecular contributors controlling these alterations remain elusive. Here, we reveal that rapid CTCF degradation generates local genome structure alterations at KMT2A and copy gains and rearrangements. We then established a conserved, coordinated interplay between DNA and histone methylation pathways that control CTCF occupancy, and in turn, KMT2A locus stability. For example, DNMT1 overexpression promotes increased H3K9 methylation, reduced CTCF occupancy, and causes KMT2A alterations. However, DNMT1 inhibition suppresses these events and KMT2A alterations caused by topoisomerase II inhibition. Locus-specific epigenome targeting demonstrated that DNA or H3K9 methylation promotes KMT2A copy gains and rearrangement, whereas targeted TET activity suppresses these events upon methylation perturbation or doxorubicin treatment. These findings identify a conserved, coordinated DNA-histone methylation axis governing KMT2A amplifications and rearrangement susceptibility, revealing biomarkers and therapeutic targets to predict and intercept these events in cancer.

cancer biology↗

bioRxiv2026

Complete genome sequence and metabolic features of Vreelandella zhaodongensis BS253: A new isolate from hypersaline lakes from Brazilian Pantanal

The urgent need for sustainable solutions to mitigate climate change has intensified research into carbon capture, utilization, and storage (CCUS) strategies. Biological approaches, particularly involving extremophilic microorganisms, offer promising alternatives to conventional methods due to their adaptability and potential for bioproduct synthesis. In this study, we report the complete genome sequencing and functional characterization of isolate BS253, derived from a hypersaline alkaline lake in Brazils Pantanal region. Using a hybrid sequencing strategy combining Oxford Nanopore long reads and Illumina short reads, we assembled a circular chromosome of 3.76 Mb and identified two plasmids. Phylogenetic and comparative genomic analyses identified the isolate as Vreelandella zhaodongensis. Digital DNA-DNA hybridization (dDDH % = 71.4%) and ANI (96,83%) values supported the designation of BS253 as a distinct subspecies of V. zhaodongensis. The genome reveals genes associated with salt and alkali tolerance, hydrocarbon and plastic degradation, and the biosynthesis of secondary metabolites. Phenotypically, BS253 is a moderately halophilic, facultatively anaerobic, Gram-negative rod exhibiting biosurfactant activity, with an emulsification index of 51.7% under defined culture conditions. These findings highlight BS253 as a metabolically versatile extremophile with potential applications in different types of industries and biotechnological CCUS systems. ImportanceMicroorganisms adapted to extreme environments represent an untapped source of biotechnologically valuable traits. Vreelandella zhaodongensis BS253, isolated from a hypersaline alkaline lake in the Brazilian Pantanal, expands the known diversity of extremophiles and offers metabolic features with relevance to sustainable bioprocesses. Its complete genome reveals genes involved in salt and alkali tolerance, plastic and hydrocarbon degradation, and the biosynthesis of biosurfactant-like compounds, positioning this strain as a promising chassis for applications in emerging carbon capture, utilization, and storage (CCUS) strategies. The ability of BS253 to produce bioemulsifying molecules under defined nutritional conditions, combined with pathways for degrading recalcitrant pollutants, reinforces its potential for environmentally friendly industrial processes. By characterizing BS253 at the genomic and physiological levels, this work provides foundational information for future exploitation of extremophiles in biotechnological innovations aimed at reducing carbon emissions and supporting circular bioeconomy initiatives.

microbiology↗

bioRxiv2022

Pan-genomic analysis shows hemizygous PTEN loss tumors are associated with immune evasion and poor outcome

In tumors, somatic mutations of the PTEN suppressor gene are associated with advanced disease, chemotherapy resistance, and poor survival. PTEN loss of function may occur by inactivating mutation, by deletion, either affecting one copy (hemizygous loss) leading to reduced gene expression or loss of both copies (homozygous) with expression absent. Various murine models have shown that minor reductions in PTEN protein levels strongly influence tumorigenesis. Most PTEN biomarker assays dichotomize PTEN (i.e. presence vs. absence) ignoring the role of one copy loss. We performed a PTEN copy number analysis of 9,793 TCGA cases from 30 different tumor types. There were 419 (4.28%) homozygous and 2484 (25.37%) hemizygous PTEN losses. Hemizygous deletions led to reduced PTEN gene expression, accompanied by increased levels of instability and aneuploidy across tumor genomes. Outcome analysis of the pan-cancer cohort showed that losing one copy of PTEN reduced survival to comparable levels as complete loss, and was associated with transcriptomic changes controlling immune response and the tumor microenvironment. Immune cell abundances were significantly altered for PTEN loss, with changes in head and neck, cervix, stomach, prostate, brain, and colon more evident in hemizygous loss tumors. These data suggest that reduced expression of PTEN in tumors with hemizygous loss leads to tumor progression and influences anticancer immune response pathways.

cancer biology↗

bioRxiv2022

Quantitative MHC class-I/-II expression levels in CDK12 mutated prostate cancer patients reveal intratumorally T cell adaptive immune response in tumors

BackgroundCDK12 inactivation is a predictive biomarker for immune checkpoint blockers (ICB) treatment response in advanced prostate cancer (PCa), but some CDK12-altered patients fail to respond to ICB. Downregulation of MHC expression has been described as a mechanism of intrinsic and acquired resistance to ICB in various cancers, but there is little information on whether MHC expression levels are altered in CDK12 defective PCa that fails to respond to ICB treatments. MethodsUsing genomics data of primary and metastatic prostate cancer from two public domain cohorts and a retrospective cohort, we investigated variation in the expression of the MHC genes and associated downstream changes in CDK12 mutated patients. The findings of public domain data were validated using transcriptomic data from a 53-patient retrospective cohort from our Institute. ResultsBased on the analysis of gene expression quartiles, we divided the tumors into "High" and "Low" expression levels of MHC-I and -II. CDK12 defective tumors with increased MHC levels showed the activation of several pathways associated with the immune system and elevated PD-L1, IDO1, and TIM3 expression. These transcriptomic findings were confirmed using expression analyses of our cohort of 53 primary PCa. There was an increased composition of CD8+ T cells, B cells, {gamma}{delta} T cells, and M1 Macrophages in CDK12 mutated tumors with elevated MHC levels based on digital cytometric analyses. In contrast, CDK12 defective tumors with decreased MHC expression were often subject to loss of heterozygosity (LOH) genomic events affecting MHC-I/-II and the HLA gene cluster on chromosome 6. CDK12 defective PCa expresses higher levels of classical MHC, has an active and inflamed tumor microenvironment, and increases the presence of effector T cells. ConclusionsReduced MHC expression may be caused by the acquisition of specific somatic genomic events that reduce the expression of antigen presentation genes. Combining CDK12 mutation, MHC expression levels, and LOH status may better predict outcomes for ICB-eligible PCa. In addition, these findings draw attention to the need to investigate therapeutic approaches for enhancing MHC expression in CDK12 defective PCa to improve ICB responses.

cancer biology↗