Current Research Interests: With the work of large consortia like FANTOM (functional annotation of the mammalian genome) and ENCODE (Encyclopedia of DNA elements), our understanding of the human genome has dramatically changed. Initially considered as “junk” DNA, it is now clear that the non-protein protein coding part, which comprises about 98 % of the ~3·109 DNA bases, is extensively transcribed and gives rise to numerous non-coding non RNAs.. Although we are only beginning to understand the complexity of their biological biological function, growing evidence suggests that at least some non-coding non coding RNAs contribute significantly to the orchestrating and fine-tuning tuning of gene expression both in health and disease. In our small group, we are mainly interested in deciphering the role role of these non-coding RNAs in the regulation of complex transcriptional networks, using hematopoiesis and immune function as experimental model systems. Within this is field, we are currently focusing focu on two different types of non-coding non RNAs, namely microRNAs As and long intergenic nonnon coding RNAs (lincRNAs). MicroRNAs (miRNAs) are small, non-coding non coding RNAs that mediate posttranscriptional silencing of a predicted 60% of protein-coding protein coding genes in mammals. Although only discovered in 1993 by Ambros and Ruvkun,, they have quickly emerged as central mediators of many, if not all biological processes. In our work, work we are trying to decipher how microRNAs influence early B lymphocyte development and, and if aberrantly expressed, promote cellular transformation (Fig. 1).To elucidate the role of individual miRNAs under physiological as well as pathological conditions, we combine gain- and loss-of-function approaches, both inin in vitrosystemsas vitro well as in gene-modified modified mouse models, models with cell biological, biochemical and molecular molec approaches. Fig. 1:Early Early B lymphocyte development is frequently used as a model system for complex transcriptional regulation. Several microRNAs have been linked to defined stage progressions, and others have been shown to promote oncogenic transformation when aberrantly expressed. However, with more than 100 microRNAs expressed in lymphocytes, their individual contribution to cellular function and how they are integrated into transcriptional networks is mostly unclear. LincRNAs, in contrast, form a heterogeneous group of long non-coding non coding RNAs transcribed from independent genomic units that do not overlap with any coding genes. Recent data implicate different modes of action for lincRNAs, such as mediating the recruitment of associated proteins to specific genes in a sequence-dependent manner, or the organization of multi-protein complexes. Other lincRNAscan act as decoys that can sequester proteins and by that interfere with their binding to other RNAs or DNA. With few exceptions, however, we are far from understanding which of the thousands of lincRNAs expressed in each cell confers a regulatory function, and if so, how their function is mediated on the molecular level. Experimentally, we combine Next Generation Sequencing for global lincRNA identification with CRISPR/Cas9-mediated loss-of-function approaches to unravel the role of individual lincRNAs in hematopoiesis and the immune system. This is complemented by a broad panel of molecular and biochemical approaches, such as RNA pulldowns, to gain mechanistic insights into lincRNA function.
© Copyright 2020