transcription factor

Definition: The genome encodes the information required for building an organism, including genes that encode proteins and functional RNAs, and more importantly, the instructions for when, where, under what conditions, and at what levels genes are expressed.

Classification

CHXs	ETSs	EYAs	HOXs	FOXs	KLFs	LIMs	LMXs
MSXs	OTXs	PAXs	PHOXs	PITXs	POUs	PPARs
SOXs	TEADs	TBXs	VSXs	ZNFs

Elaborate regulation of gene expression is a key driving force for organismal complexity (Levine and Tjian 2003).

Transcription factors (TFs) are a family of proteins that can execute the instructions for transcriptional regulation by interacting with RNA polymerases to activate or repress their actions (Maston et al. 2006).

The fidelity of transcriptional regulation ultimately relies on TFs, which can bind directly to genomic DNA with specific sequences via their DNA-binding domains, or indirectly through interactions with other DNA-binding TFs.

The regulation of most genes requires many TFs, which may form large complexes, and a TF typically regulates many genes.

In eukaryotic cells, transcription is regulated in the context of chromatin, whereby genomic DNA is packaged into nucleosomes, and TFs must compete with nucleosomes for accessibility to genomic DNA.

It was discovered early on that some loosely packaged regions of chromatin were hypersensitive to cleavage by DNase I, and these regions might harbor regulatory DNA (Weintraub and Groudine 1976).

The advent of high-throughput genomic techniques allowed systematic mapping of nucleosomes, and more recent studies showed that most genomic DNA is nucleosomal and that functional TF binding sites tend to be located in nucleosome-depleted regions (Guertin and Lis 2010; John et al. 2011; Li et al. 2011).

Nonetheless, some TFs are capable of remodeling nucleosomes in the absence of additional factors, and other TFs can recruit nucleosome remodelers to reposition or evict nucleosomes and expose TF binding sites (Berger 2007; Clapier and Cairns 2009).

Furthermore, it was reported that TF binding sites are flanked by multiple well-positioned nucleosomes (Fu et al. 2008; Valouev et al. 2011).

Transcriptional regulation has been studied at the single-gene level for several decades.

TFs recognize 8- to 21-base pair (bp) degenerate sequence motifs (Matys et al. 2003; Bryne et al. 2008), but in vivo a given TF typically only associates with a small subset of the genomic sites that match its binding motif.

Transcription factor-genome interactions

A crucial question in the field of gene regulation is whether the location at which a transcription factor binds influences its effectiveness or the mechanism by which it regulates transcription.

Comprehensive transcription factor binding maps are needed to address these issues, and genome-wide mapping is now possible thanks to the technological advances of ChIP-chip and ChIP-seq.

Genomic profiling of transcription factors gives insight into how binding specificity is achieved and what features of chromatin influence the ability of transcription factors to interact with the genome.

Classification

CHXs	ETSs	EYAs	HOXs	FOXs	KLFs	LIMs	LMXs	MSX s	OTXs
PAXs	PHOXs	PITXs	POUs	PPARs	SOXs	TBXs	VSXs	ZNFs

Pathology (Exemples)

 transcription factors in cancer
 transcription factors in developmental anomalies (developmental disorders)

Transcription factors and developmental disorders (Exemples)

 TBX5 mutations in Holt-Oram syndrome (TBXs)
 LMX1B mutations in nail-patella syndrome (LIMs)

Transcription factors in cancer (Exemples)

 transcription factor fusion gene formation by translocation
 transcription factor gene mutations

Pathology by molecular groups

CHXs
ETSs
FOXs
HOXs
LIMs
MSXs
OTXs
PAXs
PHOXs
PITXs
POUs
PPARs
SOXs
TCFs
TCF2	type 2 diabetes	renal cysts and diabetes	renal dysplasia
VSXs
TBXs
ZNFs

ChIP-seq data

ChIP-seq is a technique for mapping TF binding regions genome-wide in living cells.

The method combines chromatin immunoprecipitation (ChIP), using TF-specific antibodies, with high-throughput sequencing (seq) (Robertson et al. 2007).

Dozens of ChIP-seq data sets of mammalian TFs have been reported in the literature by individual labs (Biggin 2011; MacQuarrie et al. 2011).

The ENCODE Consortium has generated 457 ChIP-seq data sets on 119 TFs in 72 cell lines (Supplemental Table S1) and determined transcription levels, nucleosome occupancy, and DNase I hypersensitivity in a subset of these cell lines (The ENCODE Project Consortium 2011).

See also

 lineage-specific transcription factors

References

 Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors. Jie Wang et al., 2012

 Insights from genomic profiling of transcription factors. Farnham PJ. Nat Rev Genet. 2009 Sep;10(9):605-16. PMID: 1966824

 Darnell JE Jr. Transcription factors as targets for cancer therapy. Nat Rev Cancer. 2002 Oct;2(10):740-9. PMID: 12360277

 Hart SM. Modulation of nuclear receptor dependent transcription. Biol Res. 2002;35(2):295-303. PMID: 12415747

 Badis G, Berger MF, Philippakis AA, Talukder S, Gehrke AR, Jaeger SA, Chan ET, Metzler G, Vedenko A, Chen X, et al. 2009. Diversity and complexity in DNA recognition by transcription factors. Science 324: 1720–1723.

 Berger SL. 2007. The complex language of chromatin regulation during transcription. Nature 447: 407–412.

 Biggin MD. 2011. Animal transcription networks as highly connected, quantitative continua. Dev Cell 21: 611–626.