Biology subjects

Rodriguez, J. D.

Publications and source records attributed to Rodriguez, J. D..

4 recordsLinked to original sources

bioRxiv2026

Systematic identification of DNA methylation biomarkers for tumor-type-specific detection

DNA methylation biomarkers for cancer diagnostics often underperform when tumor and background tissues share epigenetic programs, or when complex specimens with mixed cellular composition dilute tumor-derived signals and increase variability. To address these limitations, we developed a gene-centric, browser-based discovery platform that integrates genome-wide methylomes with matched transcriptomes and reference layers spanning pan-cancer tissues and leukocytes, enabling background-aware filtering beyond binary tumor-normal contrasts. Candidate loci are prioritized using combined thresholds on methylation effect size and intra-group variability to penalize stochastic and heterogeneous variation. In colorectal cancer, methylation-sensitive restriction enzyme quantitative PCR (MSRE-qPCR) validation in independent tissue cohorts confirmed multiple candidate loci with AUCs of 0.81-1.00. Using the same framework, MSRE-qPCR validation distinguished hepatocellular carcinoma from cirrhotic liver, and analysis of public tumor methylomes identified subtype-specific markers in lung adenocarcinoma and squamous-cell carcinoma. This resource bridges genome-scale epigenomic discovery with clinically accessible PCR-based methylation assays.

bioinformatics↗

bioRxiv2025

The Dream and MEC NuRD Complexes reinforce SPR-5/MET-2 maternal reprogramming to maintain the germline-soma distinction

The proper coordination of transcription factors, ATP dependent chromatin remodelers and histone modifications is essential for tissue specific gene expression, but how gene expression is regulated at these different levels is not well understood. In C. elegans, H3K4 methylation that is acquired in the germline is reprorgammed at fertilization by the H3K4me1/2 demethlyase SPR-5/LSD1/KDM1A and the H3K9 methyltransferase MET-2/SETDB1/KMT2E. SPR-5/MET-2 maternal reprogramming is required to help establish the germline-soma distinction and prevent developmental delay by preventing inherited H3K4 methylation from inappropriately maintaining germline gene expression in somatic tissues. To determine if the DREAM transcriptional repressor complex and the MEC NuRD ATP dependent nucleosome remodeling and histone deacetylase complex function to reinforce SPR-5/MET-2 maternal reprogamming, we asked if loss of these complexes affects the ectopic germline transcription and developmental delay in spr-5; met-2 double mutants. We find that knocking down the DREAM or MEC NuRD complexes specifically exacerbates the developmental delay and ectopic expression of germline genes in the soma caused by loss of SPR-5 and MET-2. In addition, the DREAM and MEC NuRD complexes bind together at SPR-5/MET-2 reprogramming targets. These data suggest that the transcriptional repression of DREAM and the ATP dependent chromatin remodeling and deactylation activities of the MEC NuRD complex are required somatically to reinforce maternal histone reporgamming by SPR-5/MET-2. Thus, these data provide a novel example of how gene regulation is coordinated at multiple levels to maintain the germline-soma distinction and ensure proper development.

genetics↗

bioRxiv2023

Ectopic transcription due to inappropriately inherited histone methylation may interfere with the ongoing function of terminally differentiated cells

How mutations in histone modifying enzymes lead to neurodevelopmental disorders is unknown. We took advantage of the invariant embryonic lineage and adult nervous system in C. elegans to investigate a double mutant between spr-5/Lsd1/Kdm1a (H3K4me1/2 demethylase) and met-2/Setdb1 (H3K9 methyltransferase). We demonstrate that spr-5; met-2 double mutant worms have a severe chemotaxis defect caused by the ectopic expression of germline genes in somatic tissues. Despite this behavioral defect, we observe few embryonic lineage alterations and an intact adult nervous system. This raises the possibility that the abnormal chemotaxis behavior may be due to ongoing defects in terminally differentiated cells rather than alterations in development. Remarkably, we found that shutting off the ectopic germline expression rescues normal chemotaxis in the same spr-5; met-2 adult worms that had a chemotaxis defect earlier. This suggests that ongoing inappropriate transcription can block normal behavior in an intact nervous system. Based on these data, it is possible that the intellectual disability and altered behavior observed in human neurodevelopmental syndromes caused by mutations in histone modifying enzymes could be due to ongoing ectopic transcription and may be reversible.

developmental biology↗

bioRxiv2022

Predictive nonlinear modeling of malignant myelopoiesis and tyrosine kinase inhibitor therapy

Chronic myeloid leukemia (CML) is a blood cancer characterized by dysregulated production of maturing myeloid cells driven by the product of the Philadelphia chromosome, the BCR-ABL1 tyrosine kinase. Tyrosine kinase inhibitors (TKI) have proved effective in treating CML but there is still a cohort of patients who do not respond to TKI therapy even in the absence of mutations in the BCR-ABL1 kinase domain that mediate drug resistance. To discover novel strategies to improve TKI therapy in CML, we developed a nonlinear mathematical model of CML hematopoiesis that incorporates feedback control and lineage branching. Cell-cell interactions were constrained using an automated model selection method together with previous observations and new in vivo data from a chimeric BCR-ABL1 transgenic mouse model of CML. The resulting quantitative model captures the dynamics of normal and CML cells at various stages of the disease and exhibits variable responses to TKI treatment, consistent with those of CML patients. The model predicts that an increase in the proportion of CML stem cells in the bone marrow would decrease the tendency of the disease to respond to TKI therapy, in concordance with clinical data and confirmed experimentally in mice. The model further suggests that a key predictor of refractory response to TKI treatment is an increased probability of self-renewal of normal hematopoietic stem cells. We use these insights to develop a clinical prognostic criterion to predict the efficacy of TKI treatment and to design strategies to improve treatment response. The model predicts that stimulating the differentiation of leukemic stem cells while applying TKI therapy can significantly improve treatment outcomes.

systems biology↗