Three recent studies (described in

detail below) characte

Three recent studies (described in

detail below) characterized the relative contribution of these four transcription factors in the activation and function of lineage-specific regulatory DNA, or enhancers.[12-14] Surprisingly, despite differing approaches, all three studies demonstrated a quantitatively minor role for these four MRFs in the de novo activation of lineage-specific enhancers. In the two general models for T-cell lineage enhancer activation tested by these studies, the first step is the same: the ‘right’ combinations of environmentally activated www.selleckchem.com/products/AZD0530.html or induced transcription factors – environmental response factors (ERFs) such as STATs, interferon regulatory factors (IRFs), activated protein 1 (AP-1), nuclear factor of activated T-cell (NFAT) and nuclear factor κB (NF-κB) – bind to, and initiate expression of, master regulator factors (MRF) – Tbx21, Gata3, Rorc, Foxp3. Simultaneously these ERFs activate a set of general activation response (Th0) regulatory DNA elements, and a subset of lineage-specific (for example Th1- or Th2-specific) regulatory elements. In the second step, the MRFs either co-ordinate de novo activation of remaining lineage-specific Tanespimycin datasheet regulatory DNA allowing binding of ERFs (perhaps acting in a second wave),

or alternatively, they mainly bind to enhancers previously activated by ERFs. The critical distinction between these models is whether MRFs pioneer the activation of lineage-specific regulatory elements, or bind to regulatory elements pre-activated by ERFs. Based on recent studies, it appears MycoClean Mycoplasma Removal Kit that most lineage-specific enhancers are initially activated by ERFs or other nuclear factors expressed and functioning before the induced expression of MRFs. In particular, STATs, IRFs and AP-1 factors acting co-operatively have a prominent role in the activation of T-cell subset enhancers. To determine the relative contributions of STATs and MRFs, O’Shea and colleagues extensively characterized the enhancers of in vitro differentiated Th1 and Th2 cells with and without

the respective STATs and MRFs.[13] One exciting observation from this study was the uniqueness of the Th1-activated and Th2-activated enhancer landscapes. Just over half of all active enhancers in Th1 and Th2 cells, characterized by both H3K4me1 and p300 binding, were shared between the two lineages Considering how closely related Th1 and Th2 cells are in the context of expansive cellular diversity (and considering these particular cells derived from a homogeneous population of naive CD4 T-cells before TCR and cytokine driven in vitro differentiation), this extent of dissimilarity in their enhancer landscapes is interesting and suggests broad functional divergence and responsiveness. The likely explanation for this discrete enhancer repertoire is that differential activation of ERFs between the two lineages plays an extensive role in the activation of enhancers.

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