Biology subjects

Domingues, A. F.

Publications and source records attributed to Domingues, A. F..

5 recordsLinked to original sources

bioRxiv2023

MAT2A inhibition in AML unveils therapeutic potential of combining DNA demethylating agents with UPR targeting

Acute Myeloid Leukaemia (AML) is a heterogeneous disease of dismal prognosis, with vulnerabilities in epigenetic and metabolic regulation. DNA demethylating agents, e.g. azacytidine (AZA), are used as first-line therapy in AML patients unable to tolerate intensive chemotherapy regimens, often in combination with BCL-2 inhibitor venetoclax. However, the impact on survival is limited, indicating the need for alternative therapeutic strategies. Methyl-group usage for epigenetic modifications depends on methionine availability and MAT2A-driven conversion to S-adenosyl-methionine. Methyl-group production is a vulnerability in multiple tumours, including AML, and has been variably linked to impairment of different histone methyl-modifications. In contrast, we herein align MAT2A effects in AML with DNA methylation and proteostasis. We show that MAT2A inhibition can be mimicked by combining AZA with unfolded protein response (UPR) activation through targeting of valosin-containing protein (VCP)/P97. Combined AZA and P97 inhibition exceeded AZA-driven restriction of human AML cell expansion, and specifically impaired colony-formation and maintenance of CD34+ patient blasts, suggesting targeting of AML stem/progenitor-like cells. Overall, our data support combined targeting of DNA methylation and the UPR as a promising therapeutic strategy in AML.

cancer biology↗

bioRxiv2021

Transcriptional variability accelerates pre-leukemia by cell diversification and perturbation of protein synthesis

Transcriptional variability facilitates stochastic cell diversification and can in turn underpin adaptation to stress or injury. We hypothesize that it may analogously facilitate progression of pre-malignancy to cancer. To investigate this, we initiated pre-leukemia in mouse cells with enhanced transcriptional variability due to conditional disruption of the histone lysine acetyltransferase gene Kat2a. By combining single-cell RNA-sequencing of pre-leukemia with functional analysis of transformation, we show that Kat2a loss results in global variegation of cell identity and accumulation of pre-leukemic cells. Leukemia progression is subsequently facilitated by destabilization of ribosome biogenesis and protein synthesis, which confer a transient transformation advantage. The contribution of transcriptional variability to early cancer evolution reflects a generic role in promoting cell fate transitions, which, in the case of well-adapted malignancies, contrastingly differentiates and depletes cancer stem cells. In other words, transcriptional variability confers forward momentum to cell fate systems, with differential multi-stage impact throughout cancer evolution. One-sentence summaryLoss of Kat2a enhances transcriptional variability of ribosome biosynthetic programs and transiently accelerates pre-leukemia

cancer biology↗

bioRxiv2020

Unique roles of ATAC and SAGA KAT2A complexes in normal and malignant hematopoiesis

Epigenetic histone modifiers are key players in cell fate decisions. Significant research has focused on their enzymatic activity, but less is known about the contextual role of the complexes they integrate. We focus on KAT2A, a histone acetyltransferase we recently associated with leukemia stem cell maintenance, and which participates in ATAC and SAGA complexes. We show that ATAC is uniquely required for maintenance of normal and leukemia stem and progenitor cells, while SAGA more specifically contributes to cell identity. This dichotomy sets a paradigm for investigating epigenetic activities in their macromolecular context and informs epigenetic regulator targeting for translational purposes.

cell biology↗

bioRxiv2018

Loss Of Kat2a Enhances Transcriptional Noise And Depletes Acute Myeloid Leukemia Stem-Like Cells

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective myelo-monocytic differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation and by hijacking normal chromatin regulation. Kat2a is a histone acetyltransferase central to promoter activity that we recently associated with stability of pluripotency networks, and identified as a genetic vulnerability in AML. Through combined chromatin profiling and single-cell transcriptomics, we demonstrate that Kat2a contributes to leukemia propagation through homogeneity of transcriptional programs and preservation of leukemia stem-like cells. Kat2a loss reduces transcriptional bursting frequency in a subset of gene promoters, generating enhanced variability of transcript levels but minimal effects on mean gene expression. Destabilization of target programs shifts cellular equilibrium out of self-renewal towards differentiation. We propose that control of transcriptional variability is central to leukemia stem-like cell propagation, and establish a paradigm exploitable in different tumors and at distinct stages of cancer evolution.

cancer biology↗

bioRxiv2018

Histone Acetyltransferase Kat2a Stabilises Pluripotency with Control of Transcriptional Heterogeneity

Cell fate transitions in mammalian stem cell systems have often been associated with transcriptional heterogeneity, however existing data have failed to establish a functional or mechanistic link between the two phenomena. Experiments in unicellular organisms support the notion that transcriptional heterogeneity can be used to facilitate adaptability to environmental changes and have identified conserved chromatin-associated factors that modulate levels of transcriptional noise. Herein, we show destabilisation of pluripotency-associated gene regulatory networks through increased transcriptional heterogeneity of mouse embryonic stem cells in which paradigmatic histone acetyl-transferase, and candidate noise modulator, Kat2a (yeast orthologue Gcn5) has been inhibited. Functionally, network destabilisation associates with reduced pluripotency and accelerated mesendodermal differentiation, with increased probability of transitions into lineage commitment. Thus, we functionally link transcriptional heterogeneity to cell fate transitions through manipulation of the histone acetylation landscape of mouse embryonic stem cells and establish a general paradigm that could be exploited in other normal and malignant stem cell fate transitions.

developmental biology↗