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.