| dc.contributor.advisor | Eichele, Gregor Prof. Dr. | |
| dc.contributor.author | Petkau, Nikolai | |
| dc.date.accessioned | 2019-12-11T09:33:32Z | |
| dc.date.available | 2019-12-11T09:33:32Z | |
| dc.date.issued | 2019-12-11 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0005-12C8-5 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7765 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7765 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | TIP60 acetylation of BMAL1 links positive and negative arms of the molecular circadian clock | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Eichele, Gregor Prof. Dr. | |
| dc.date.examination | 2019-12-04 | |
| dc.description.abstracteng | Many physiological processes exhibit circadian rhythms driven by cellular clocks composed of interlinked activating and repressing elements. The far-reaching influence of the circadian organization is illustrated by the fact that in each tissue ~10% of the transcriptome is under the control of the circadian clock. Positive components are heterodimers of CLOCK and BMAL1 that bind to E-box promoter elements of Period and Cryptochome genes that encode repressor proteins CRY and PER. However, important issues that the transcriptional/translational feedback loop leave unresolved are (1) how binding of CLOCK-BMAL1 heterodimers to E-box promoter elements results in RNA Pol II-mediated transcription and (2) how exactly CRY proteins interfere with this process. Transcription is a highly complex process that is regulated at multiple levels. Well-recognized, rate-limiting step is the RNA Pol II release from promoter-proximal pause sites, which serves as a checkpoint, allowing rapid and synchronous expression of genes. This pause release of RNA Pol II and the transition to productive elongation requires the activity of the P-TEFb. P-TEFb is recruited by interaction with specific factors such as BRD4 to gene promoters. BRD4 binds through its bromo-domains to acetylated lysines of histones and of transcription factors present at the promoters, thereby bringing P-TEFb to the site of action. Acetyltransferases that acetylate BRD4 binding partners play an important role in regulating RNA Pol II pause release. Of particular relevance for the present study is the lysine acetyltransferase TIP60. TIP60 is an essential protein and is involved in a multitude of cellular processes that depend on lysine acetylation of histone and non-histone proteins.
To investigate the temporal regulation of CLOCK-BMAL1-mediated transcription, mouse genetic approaches and analyses of interactions of key circadian proteins with each other and with E-box-containing clock gene promoters were combined. This approach provided evidence that the positive and negative phases of the circadian oscillator are linked through the acetyltransferase TIP60. The circadian clock cycle is initiated by BMAL1 binding to E-boxes of clock genes followed by a TIP60-mediated acetylation of chromatin bound BMAL1. This acetylation triggers recruitment of the BRD4-P-TEFb complex to E-box-containing circadian promoters leading to RNA Pol II pause release and productive elongation of circadian transcripts, including those encoding CRY and PER proteins. The study further shows that CRY repressors compete with TIP60 for BMAL1 to prevent TIP60 from acetylating BMAL1, thereby abolishing the binding of BRD4-P-TEFb complexes to circadian promoters and thus inhibiting productive transcript elongation. This competition characterizes the repressive limb of the clock cycle and eventually culminates in a complete cessation of BMAL1 acetylation and, thus, to the termination of clock gene transcription. Taken together, the experiments suggest that control of BRD4-P-TEFb recruitment to E-box-containing circadian promoters is a novel temporal checkpoint in the circadian clock cycle. | de |
| dc.contributor.coReferee | Urlaub, Henning Prof. Dr. | |
| dc.subject.eng | circadian clock + transcription + Pol II pause release | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-12C8-5-6 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1685364659 | |