Biology subjects

Bergbrede, T.

Publications and source records attributed to Bergbrede, T..

2 recordsLinked to original sources

bioRxiv2022

Reduced mitochondrial transcription sensitizes acute myeloid leukemia cells to BCL-2 inhibition

Overcoming drug-resistance and the subsequent relapse that often occurs with monotherapy is crucial in the treatment of acute myeloid leukemia. We here demonstrate that therapy-resistant leukemia initiating cells can be targeted using a novel inhibitor of mitochondrial transcription (IMT). The compound inhibits mitochondrial RNA polymerase activity and sensitizes the resistant population to the induction of apoptosis. In vitro studies on acute myeloid leukemia cells demonstrate that IMT prevents cell proliferation, and together with a selective BCL-2 inhibitor, venetoclax, induces apoptosis and suppress oxidative phosphorylation (OXPHOS) synergistically. AML mouse models treated with IMT in combination with venetoclax show prolonged survival in venetoclax-resistant models. Our findings suggest that certain therapy-resistant leukemia cell populations display a unique dependency on mitochondrial transcription and can be targeted with IMT.

cancer biology↗

bioRxiv2021

OCT4 interprets and enhances nucleosome flexibility

Pioneer transcription factors are proteins that induce cellular identity transitions by binding to inaccessible regions of DNA in nuclear chromatin. They contribute to chromatin opening and recruit other factors to regulatory DNA elements. The structural features and dynamics modulating their interaction with nucleosomes are still unresolved. From a combination of experiments and molecular simulations, we reveal here how the pioneer factor and master regulator of pluripotency, Oct4, interprets and enhances nucleosome structural flexibility. The magnitude of Oct4s impact on nucleosome dynamics depends on the binding site position and the mobility of the unstructured tails of nucleosomal histone proteins. Oct4 propagates and stabilizes open nucleosome conformations by specific sequence recognition and nonspecific DNA exploration. Our findings provide a structural basis for the versatility of transcription factors in engaging with nucleosomes and have implications for understanding how pioneer factors induce chromatin dynamics.

biophysics↗