Hoxa2 selectively enhances Meis binding to change a branchial arch ground state.

Hox transcription factors (TFs) are essential for vertebrate development, but how these evolutionary conserved proteins function in vivo remains unclear. Because Hox proteins have notoriously low binding specificity, they are believed to bind with cofactors, mainly homeodomain TFs Pbx and Meis, to select their specific targets. We mapped binding of Meis, Pbx, and Hoxa2 in the branchial arches, a series of segments in the developing vertebrate head. Meis occupancy is largely similar in Hox-positive and -negative arches. Hoxa2, which specifies second arch (IIBA) identity, recognizes a subset of Meis prebound sites that contain Hox motifs. Importantly, at these sites Meis binding is strongly increased. This enhanced Meis binding coincides with active enhancers, which are linked to genes highly expressed in the IIBA and regulated by Hoxa2. These findings show that Hoxa2 operates as a tissue-specific cofactor, enhancing Meis binding to specific sites that provide the IIBA with its anatomical identity.

Cross-talk between DNA methylation and active histone modifications regulates aberrant expression of ZAP70 in CLL.

Zeta-associated protein of 70 kD (ZAP70) is a recognized adverse prognostic marker in chronic lymphocytic leukaemia (CLL) associated with enhanced B-cell receptor signalling, significantly more aggressive disease course and poor overall survival. Zeta-associated protein of 70 kD is ordinarily expressed in T cells where it has a crucial role in T-cell receptor signalling, whereas its aberrant expression in CLL leads to enhanced B-cell receptor signalling and significantly more aggressive disease course. Although much is known about the activation of ZAP70 following engagement of T-cell receptor, there are little data on the regulation of ZAP70 gene expression in normal T cells or CLL. To understand the molecular events underpinning epigenetic regulation of ZAP70 gene in CLL, we have defined ZAP70 promoter region and outlined the regions crucial in regulating the gene activity. Following a direct comparison of ZAP70+ and ZAP70- primary CLLs, we show ZAP70 promoter in expressing CLLs to be associated with a spectrum of active histone modifications, some of which are tightly linked to aberrant DNA methylation in CLL. Cross-talk between histone modifications and reduced DNA methylation culminates in transcriptional de-repression of ZAP70. Moreover, treatment with histone deacetylase (HDAC) and DNA methylation inhibitors results in recovery of ZAP70 expression, which provides a possible explanation for the failure of HDAC inhibitors in CLL treatment and might serve as a cautionary warning for their future use in treatment of this leukaemia.

ZAP70 in chronic lymphocytic leukaemia.

The protein tyrosine kinase zeta-chain associated protein kinase (ZAP70), normally expressed in T cells and a subset of B cells, is solely expressed in poor prognosis chronic lymphocytic leukaemia and implicated in enhanced B cell receptor signalling. As a result, the expression of this protein provides an ideal prognostic marker for the disease. A previous study has shown differential CpG methylation of a 5' region of ZAP70 in leukaemic lymphoid cells, although no further epigenetic studies have been reported. Further investigation into the expression of ZAP70 may therefore provide targets for therapies.