|
 
- 积分
- 429
- 威望
- 429
- 包包
- 1768
|
INTRODUCTION, u, T: ~- p' w7 x$ S8 I4 D6 ^
The maintenance of ES cell self-renewal requires a network of transcription factors, including Oct4, Sox2, Nanog, Esrrb, Tbx3, and Tcf3 (Chen et al., 2008; Ivanova et al., 2006; Kim et al., 2008; Tam et al., 2008). These factors participate in auto- and cross-regulatory interactions to increase their own expression and that of other self-renewal-associated genes while repressing genes that promote differentiation. Perturbation of these factors collapses the self-renewal circuitry and triggers specific or mixed lineage differentiation (Ivanova et al., 2006). In contrast to the numerous transcription factors, only a handful of chromatin regulators that are important for self-renewal have been characterized (Loh et al., 2007; Pasini et al., 2007; Schaniel et al., 2009).
7 K+ x& K. w" y* O$ a+ k9 W ES cells harbor an open, transcriptionally permissive chromatin that allows for efficient epigenomic remodeling during lineage commitment (Efroni et al., 2008). However, factors regulating this "hyperdynamic" epigenetic configuration remain poorly under-stood. ES cells also contain "bivalent domains" where nucleosomes are marked by trimethylation at histone3-lysine27 (H3K27me3) and histone3-lysine4 (H3K4me3) (Bernstein et al., 2006). The Polycomb group (PcG) complex mediates H3K27me3, correlated with gene repression (Boyer et al., 2006). In contrast, the Trithorax group (trxG) complex mediates H3K4me3, generally correlated with gene activation (Ringrose and Paro, 2004). Although PcG has been extensively investigated in the maintenance of ES cell self-renewal, pluripotency, and somatic cell reprogramming, there exists little complementary information for trxG-associated members. This imbalance of knowledge represents a significant shortcoming in the under-standing of the roles played by trimethylated H3K4 and H3K27 in regulating the ES cell identity. Moreover, it remains to be shown whetherthe well-established transcriptional network can functionally interact with epigenetic regulators to maintain pluripotency and, more importantly, which factors mediate such interactions.3 J3 q, Y9 c/ b8 b; v+ a
An unresolved question in chromatin biology is the manner by which generic histone modification complexes, like PcG and trxG, become targeted to specific genomic loci to direct specific gene regulatory functions (Schuettengruber et al., 2007). This is especially intriguing in the context of ES cells. For example, Chd1，a chromodomain-helicase-DNA-binding protein that is not specific to ES cells, was recently described to be essential for pluripotency and reprogramming (Gaspar-Maia et al., 2009). The factor(s) or mechanism(s) conferring such functional specificity to epigenetic regulators remains unknown. Moreover, it is unclear how ectopic expression of four transcription factors一Oct4, Sox2, KIf4, and c-Myc (OSKM)一can reprogram somatic cells to iPS cells with epigenomes that are largely indistinguishable from ES cells (Carvajal-Vergara et al., 2010; Tsai et al., 2010). This is especially pertinent to the re-establishment of the bivalent signature. Interestingly, although the OSKM-iPS methodology has been replaced by various combinations of factors or small molecules, Oct4 remains the sole factor that, until recently, could not be substituted/omitted (Heng et al., 2010). Accordingly, we reasoned that the resetting of the somatic epigenome must be achieved through the activity of Oct4-interacting proteins and/or Oct4 target genes.* s4 F3 U m% i! h- l$ l% M
Protein complexes of the Set/MLL histone methyltransferase (HMT)family are mammalian homologs of trxG that function as conserved, multisubunit ensembles to catalyze the methylation of H3K4. The human MLL gene, which contains a SET domain, was first identified based on translocations that are commonly associated with the pathogenesis of multiple forms of hematological malignancies (Shilatifard, 2006). Notably, Set/MLL proteins alone are catalytically inactive but require core subunits一WdrS, Ash21 and Rbbp5一that are related to components of the yeast Set1 complex (Dou et al., 2006). The Rbbp5 and Ash21 heterodimer directly participates in HMT activity of the M LL1 complex (Cao et al., 2010). Ash21 is required for mouse embryogenesis（Taylor et al., 2010) and proper X-inactivation (Pullirsch et al., 2010), whereas diminished recruitment of Rbbp5 is found in patients with Wiskott-Aldrich syndrome (Stoller et al., 2010). Other trxG-associated cofactors such as Menin, Hcf1， and Cxxc1 have been implicated in processes like pancreaticβcell growth (Karnik et al., 2007), tumorigenesis (Lairmore and Chen, 2009), apoptosis（Tyagi and Herr, 2009), and euchromatin formation (Thomson et al., 2010). In particular, Wdr5 is a key component of trxG acting as a "presenter" of the H3K4 residue and is indispensible for Set/MLL complex assembly and effective HMT activity (Dou et al., 2006). It was shown that Wdr5 interacts with H3K4me2 and mediates transition to the trimethylated state (Wysocka et al., 2005). However, it was also shown that Wdr5 is unable to distinguish between different H3K4 methylation states (Couture et al., 2006). Although Wdr5 function is required for vertebrate development (Wysocka et al., 2005) and osteoblast differentiation (Zhu et al., 2008), its role in ES or iPS cells remains to be determined.0 |% R' p! r8 U/ X+ a
|
|
发表于 2011-4-14 19:17
7 e2 P# s, ]( J( n' v; H3 V