Uwe Ohler

Max Delbruck Center for Molecular Medicine, and
Humboldt University, Berlin

E-mail: uwe.ohler(at)mdc-berlin.de

For more information and contact visit the Ohler lab website.

Georg Stoecklin

Mannheim Institute for Innate Immunoscience (MI3)
Medical Faculty Mannheim of Heidelberg University, and
Center for Molecular Biology of Heidelberg University (ZMBH)

E-mail: georg.stoecklin(at)medma.uni-heidelberg.de

For more information and contact visit the Stoecklin lab website.

Abstract

Acetylation of histones and transcription-associated proteins is known to exert a pervasive effect on epigenetic and transcriptional regulation of gene expression. We discovered that the histone acetyltransferases p300/CBP and histone deacetylases HDAC1&2 also have profound effects at the posttranscriptional level by exerting widespread control over poly(A) RNA stability. The regulatory switch is based on acetylation of the CCR4-CAF1-NOT deadenlyase complex, and appears to promote a dynamic mode of gene expression where active transcription is coupled to rapid mRNA degradation. In parallel, we also advanced computational methods for the identification RBP target sites from crosslinking and immunoprecipitation (CLIP) data, and developed tools for accurate assignment of open reading frames based on ribosome footprinting (Ribo-Seq).

Within the SPP 1935, we are currently characterizing novel components of the CCR4-CAF1-NOT complex, based on quantitative purification of the complex through endogenously tagged NOT1. We pursue acetylation-dependent changes in the composition of the CCR4-CAF1-NOT complex as well as RBPs that are controlled by acetylation. To characterize acetylation-induced alterations in protein synthesis, we further develop computational approaches for the quantification of translation changes based on Ribo-Seq data. Thereby, we uncover mechanistic principles by which acetylation controls gene expression at the posttranscriptional level, and provide the community with advanced computational tools for translatome analysis.

Project-related publications

Poetz F, Corbo J, Levdansky Y, Spiegelhalter A, Lindner D, Magg V, Lebedeva S, Schweiggert J, Schott J, Valkov E, Stoecklin G (2021) RNF219 attenuates global mRNA decay through inhibition of CCR4-NOT complex-mediated deadenylation. Nat Commun 12: 7175.

Calviello L, Hirsekorn A, Ohler U (2020) Quantification of translation uncovers the functions of the alternative transcriptome. Nat Struct Mol Biol. 27:717-725

Haneke K, Schott J, Lindner D, Kruse Hollensen A, Kroun Damgaard C, Mongis C, Knop M, Palm W, Ruggieri A, Stoecklin G (2020) CDK1 couples proliferation with protein synthesis. J Cell Biol 219: e201906147.

Mukherjee N, Wessels HH, Lebedeva S, Sajek M, Ghanbari M, Garzia A, Munteanu A, Yusuf D, Farazi T, Hoell JI, Akat KM, Akalin A, Tuschl T, Ohler U (2019) Deciphering human ribonucleoprotein regulatory networks. Nucleic Acids Res 47: 570-581

Lafarga V, Sung HM, Haneke K, Roessig L, Pauleau AL, Bruer M, Rodriguez-Acebes S, Lopez-Contreras AJ, Gruss OJ, Erhardt S, Mendez J, Fernandez-Capetillo O, Stoecklin G (2019) TIAR marks nuclear G2/M transition granules and restricts CDK1 activity under replication stress. EMBO Rep 20: e46224.

Munteanu A, Mukherjee N, Ohler U (2018) SSMART: sequence-structure motif identification for RNA-binding proteins. Bioinformatics 34: 3990-3998.

Drewe-Boss P, Wessels HH, Ohler U (2018) omniCLIP: probabilistic identification of protein-RNA interactions from CLIP-seq data. Genome Biol 19: 183.

Mukherjee N, Calviello L, Hirsekorn A, de Pretis S, Pelizzola M, Ohler U (2017) Integrative classification of human coding and noncoding genes through RNA metabolism profiles. Nat Struct Mol Biol 24: 86-96.

Sharma S, Poetz F, Bruer M, Ly-Hartig TBN, Schott J, Séraphin B, Stoecklin G. (2016) Acetylation-Dependent Control of Global Poly-A RNA Degradation by CBP/p300 and HDAC1/2. Mol Cell 63:927-38.

Leppek K, Schott J, Reitter S, Poetz F, Hammond MC, Stoecklin G. (2013) Roquin Promotes Constitutive mRNA Decay via a Conserved Class of Stem-Loop Recognition Motifs. Cell 153:869-81.