Biology subjects

Gudmundsson, K. O.

Publications and source records attributed to Gudmundsson, K. O..

3 recordsLinked to original sources

bioRxiv2025

MLL1 complex is a critical regulator of fetal hemoglobin repression

Increasing fetal-type hemoglobin (HbF) expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and {beta}-thalassemia. We have identified MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A, encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in {gamma}- and {varepsilon}-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A were readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their {gamma}- and {varepsilon}-globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. These findings underscore a critical role of MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for sickle cell disease and {beta}-thalassemia.

developmental biology↗

bioRxiv2024

Id1 Promotes Clonal Hematopoiesis in Mice with Tet2 Loss of Function

Hematopoietic malignancies emerge through the gradual acquisition of genetic mutations within hematopoietic stem and progenitor cells (HSPCs). Mutations that occur early in disease progression impart a selective growth advantage to HSPCs, which allows them to expand and contribute to a substantial percentage of mature blood cells. This increased expansion is termed clonal hematopoiesis (CH) and is a preleukemic phase associated with an increased risk of developing leukemia. Inhibitor of DNA binding 1 (ID1) protein is a transcriptional regulator of proliferation/differentiation of neuronal, muscle, hematopoietic and other cells, and is frequently overexpressed in cancer. Id1 is expressed at low levels in normal HSCs and is induced by growth factors and other mediators of inflammatory stress and promotes HSPC proliferation in vitro and in vivo. Since chronic inflammation is associated with the progression of hematopoietic malignancies, reducing Id1 expression during CH may be therapeutic. Mutations in TET2 are frequently observed in patients with CH, and Tet2-/-mice develop CH that progress to hematopoietic malignancies. Id1 is upregulated in murine Tet2-/- HSPCs and in AML, CMML and MDS patient samples with TET2 mutations. Genetic ablation of Id1 in Tet2-/- HSPCs reduces HSPC expansion/self-renewal/CH, extramedullary hematopoiesis, myeloid skewing, genetic instability and delays the onset of disease. Mechanistically, p16 expression, senescence and apoptosis were increased and proliferation decreased in Tet2-/-; Id1-/- HSPCs. Thus, ID1 may represent a potential therapeutic target to reduce CH, hematopoietic hyperplasia, and delay the onset of disease. One Sentence SummaryGenetic ablation of Id1 in Tet2-/- mice rescues clonal hematopoiesis by increasing CDKI expression, apoptosis, senescence, and differentiation, and reducing cell growth.

cancer biology↗

bioRxiv2018

Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology

Genes implicated in autism spectrum disorder (ASD) are enriched with chromatin regulators, but the mechanisms leading to the abnormal behavior and cognition are still unclear. Animal models are crucial for studying the effects of mutations on brain function and behavior. We generated conditional knockout mice with brain-specific mutation in Pogz, a heterochromatin regulator recurrently mutated in ASD and other neurodevelopmental disorders, and demonstrated that these mice display phenotypes that resemble the human condition. Pogz deficiency led to smaller brain, growth impairment, motor learning deficits, and increased social interactions that mimic the human overly friendly phenotype. At the molecular level, reporter assay indicated that POGZ functions as a negative regulator of transcription through its interaction with HP1 proteins. In accordance, we found a significant upregulation of gene expression, most notably in the cerebellum. Furthermore, Pogz deficiency was associated with a significant reduction in the firing frequency of simple and complex spikes in cerebellar Purkinje cells with no changes in their intrinsic properties. Overall, our findings support a mechanism linking heterochromatin dysregulation to cerebellar circuit dysfunction and to motor and social abnormalities in ASD.

neuroscience↗