Identifying transcriptional cis-regulatory modules in animal genomes
#MMPMID25704908
Suryamohan K
; Halfon MS
Wiley Interdiscip Rev Dev Biol
2015[Mar]; 4
(2
): 59-84
PMID25704908
show ga
Gene expression is regulated through the activity of transcription factors (TFs)
and chromatin-modifying proteins acting on specific DNA sequences, referred to as
cis-regulatory elements. These include promoters, located at the transcription
initiation sites of genes, and a variety of distal cis-regulatory modules (CRMs),
the most common of which are transcriptional enhancers. Because regulated gene
expression is fundamental to cell differentiation and acquisition of new cell
fates, identifying, characterizing, and understanding the mechanisms of action of
CRMs is critical for understanding development. CRM discovery has historically
been challenging, as CRMs can be located far from the genes they regulate, have
few readily identifiable sequence characteristics, and for many years were not
amenable to high-throughput discovery methods. However, the recent availability
of complete genome sequences and the development of next-generation sequencing
methods have led to an explosion of both computational and empirical methods for
CRM discovery in model and nonmodel organisms alike. Experimentally, CRMs can be
identified through chromatin immunoprecipitation directed against TFs or histone
post-translational modifications, identification of nucleosome-depleted 'open'
chromatin regions, or sequencing-based high-throughput functional screening.
Computational methods include comparative genomics, clustering of known or
predicted TF-binding sites, and supervised machine-learning approaches trained on
known CRMs. All of these methods have proven effective for CRM discovery, but
each has its own considerations and limitations, and each is subject to a greater
or lesser number of false-positive identifications. Experimental confirmation of
predictions is essential, although shortcomings in current methods suggest that
additional means of validation need to be developed. For further resources
related to this article, please visit the WIREs website. CONFLICT OF INTEREST:
The authors have declared no conflicts of interest for this article.
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