ORCID Profile
0000-0002-4149-0478
Current Organisations
Friedrich Miescher Institute for Biomedical Research
,
Friedrich Miescher Institute
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Publisher: Springer Science and Business Media LLC
Date: 29-06-2023
DOI: 10.1038/S41594-023-01021-8
Abstract: The genomic binding sites of the transcription factor (TF) and tumor suppressor p53 are unusually erse with regard to their chromatin features, including histone modifications, raising the possibility that the local chromatin environment can contextualize p53 regulation. Here, we show that epigenetic characteristics of closed chromatin, such as DNA methylation, do not influence the binding of p53 across the genome. Instead, the ability of p53 to open chromatin and activate its target genes is locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated histone 3 lysine 4 (H3K4), thereby preferentially localizing to those p53 sites that reside in closed chromatin, whereas it is deterred from accessible chromatin by H3K4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to affect gene expression as a function of the local chromatin state. These findings link H3K4 methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors that locally modulate TF function.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-06-2020
Abstract: Cell identity is defined by gene expression patterns that are established through the binding of specific transcription factors. However, nucleosomal units limit access of transcription factors to specific DNA motifs within the mammalian genome. To study how transcription factors bind such chromatinized, nucleosome-embedded motifs, Michael et al. focused on the pluripotency factors OCT4 and SOX2. They systematically quantified the relative affinities of these factors at different motif positions throughout the nucleosome, enabling structure determination of OCT4-SOX2–bound nucleosomes by cryo–electron microscopy. OCT4 and SOX2 bound cooperatively to strengthen DNA-binding affinity and resulted in DNA distortions that destabilized the nucleosome. This analysis reveals position-dependent binding modes that were validated in vivo, providing insights on how transcription factors read out chromatinized motifs. Science , this issue p. 1460
Publisher: Springer Science and Business Media LLC
Date: 10-09-2020
DOI: 10.1038/S41586-020-2750-6
Abstract: The DNA sensor cyclic GMP-AMP synthase (cGAS) initiates innate immune responses following microbial infection, cellular stress and cancer
Publisher: Springer Science and Business Media LLC
Date: 05-07-2023
DOI: 10.1038/S41586-023-06282-3
Abstract: The basic helix–loop–helix (bHLH) family of transcription factors recognizes DNA motifs known as E-boxes (CANNTG) and includes 108 members 1 . Here we investigate how chromatinized E-boxes are engaged by two structurally erse bHLH proteins: the proto-oncogene MYC-MAX and the circadian transcription factor CLOCK-BMAL1 (refs. 2,3 ). Both transcription factors bind to E-boxes preferentially near the nucleosomal entry–exit sites. Structural studies with engineered or native nucleosome sequences show that MYC-MAX or CLOCK-BMAL1 triggers the release of DNA from histones to gain access. Atop the H2A–H2B acidic patch 4 , the CLOCK-BMAL1 Per-Arnt-Sim (PAS) dimerization domains engage the histone octamer disc. Binding of tandem E-boxes 5–7 at endogenous DNA sequences occurs through direct interactions between two CLOCK-BMAL1 protomers and histones and is important for circadian cycling. At internal E-boxes, the MYC-MAX leucine zipper can also interact with histones H2B and H3, and its binding is indirectly enhanced by OCT4 elsewhere on the nucleosome. The nucleosomal E-box position and the type of bHLH dimerization domain jointly determine the histone contact, the affinity and the degree of competition and cooperativity with other nucleosome-bound factors.
Location: Switzerland
No related grants have been discovered for Joscha Weiss.