Biology subjects

Ezponda, T.

Publications and source records attributed to Ezponda, T..

4 recordsLinked to original sources

bioRxiv2024

KDM6A Regulates Immune Response Genes in Multiple Myeloma

The histone H3K27 demethylase KDM6A is a tumor suppressor in multiple cancers, including multiple myeloma (MM). We created isogenic MM cells disrupted for KDM6A and tagged the endogenous protein to facilitate genome wide studies. KDM6A binds genes associated with immune recognition and cytokine signaling. Most importantly, KDM6A binds and activates NLRC5 and CIITA encoding regulators of Major Histocompatibility Complex (MHC) genes. Patient data indicate that NLRC5 and CIITA, are downregulated in MM with low KDM6A expression. Chromatin analysis shows that KDM6A binds poised and active enhancers and KDM6A loss led to decreased H3K27ac at enhancers, increased H3K27me3 levels in body of genes bound by KDM6A and decreased gene expression. Reestablishing histone acetylation with an HDAC3 inhibitor leads to upregulation of MHC expression, offering a strategy to restore immunogenicity of KDM6A deficient tumors. Loss of Kdm6a in murine RAS-transformed fibroblasts led to increased growth in vivo associated with decreased T cell infiltration. Statement of significanceWe show that KDM6A participates in immune recognition of myeloma tumor cells by directly regulating the expression of the master regulators of MHC-I and II, NLRC5 and CIITA. The expression of these regulators can by rescued by the HDAC3 inhibitors in KDM6A-null cell lines.

cancer biology↗

bioRxiv2021

Transcriptional regulation of HSCs in Aging and MDS reveals DDIT3 as a Potential Driver of Transformation

Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in elderly individuals. In this work, we analyzed the transcriptome of human HSCs purified from young and elderly healthy donors, as well as MDS patients, identifying transcriptional alterations following eight different patterns of expression. While aging-associated lesions seemed to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detected the upregulation of the transcription factor DDIT3. Overexpression of DDIT3 in human healthy HSCs induced an MDS-like transcriptional state, and a delay in erythropoiesis. Such effect was associated with downregulation of transcription factors required for normal erythropoiesis, and with a failure in the activation of their transcriptional programs. Moreover, DDIT3 knockdown in CD34+ cells from MDS patients with anemia was able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythropoiesis characterizing MDS patients. STATEMENT OF SIGNIFICANCEThis study defines how human aging and MDS development are characterized by transcriptional alterations in HSCs that follow different patterns, some of which may contribute to myeloid transformation. Among them, we demonstrate how MDS-specific upregulation of DDIT3 in HSCs induces dyserythropoiesis, while its knockdown in HSPCs from MDS patients restores proper erythroid differentiation.

cancer biology↗

bioRxiv2021

Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single cell resolution

Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we used single cell RNA sequencing (scRNAseq) to characterize an enriched population of human hematopoietic stem and progenitor cells (HSPC) obtained from young and elderly healthy individuals. Based on their transcriptional profile, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain age-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks and detected regulons that were specifically active in elderly individuals. Using previous findings in healthy cells as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome (MDS) and detected specific alterations of the expression dynamics of genes involved in erythroid differentiation in all patients with MDS such as TRIB2. In addition, the comparison between transcriptional programs and GRN regulating normal HSPCs and MDS HSPCs allowed identification of regulons that were specifically active in MDS cases such as SMAD1, HOXA6, POU2F2 and RUNX1 suggesting a role of these TF in the pathogenesis of the disease. In summary, we demonstrate that the combination of single cell technologies with computational analysis tools enable the study of a variety of cellular mechanisms involved in early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients.

genomics↗

bioRxiv2019

Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma

Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting co-regulated adjacent genes. Among target genes upregulated by this process, we found members of the NOTCH, NFkB, mTOR1 signaling and p53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status, and in addition identified PRDM5 as a novel essential gene for MM. Collectively our data indicates that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.

cancer biology↗