Having established that binding to cell type-specific peak regions appears to involve direct interaction with DNA, the question arises as to why some regions are only bound in one or the other cell type, and whether indeed cell type-specific TFs play a role in making these regions accessible for binding by the shared TFs.
One possible explanation may come from the activation of cell-specific proteases capable of degrading TGFBI (Wen et al, 2011), such as plasmin (Ween et al, 2011), or from its binding to cell type-restricted integrins, leading to activation different cellular responses (Thapa et al, 2007).
Similarly, inhibin A, the heterodimer of INHA and INHBA gene products, antagonises the anti-proliferative action of activin A by competitive binding to cell surface activin type II receptors (ActRIIA/B) and inhibits downstream signalling in liver cells (Xu et al, 1995; Lewis et al, 2000; Massague, 2000).
In addition, peptides mediating binding to the cell type of interest can be identified by random phage display library screening and subsequently be introduced into an AAV capsid region critical for receptor binding.
Alternatively or in addition, peptides mediating binding to the cell type of interest can be identified by random phage display library screening and subsequently be introduced into an AAV capsid region critical for receptor binding [6], [7], [8], [9], [10], [11], [12].
This observation therefore suggested that, just as for those regions bound in both cell types, direct DNA binding via established consensus motifs plays an important role for the binding of shared TFs to cell type-specific regions.
Whether proteinaceous receptors are involved in binding of RTX toxins to cell types other than leukocytes remains an open question.
In-depth experimental and computational analysis revealed: (i) largely non-overlapping binding profiles of shared TFs which are predictive of differential gene expression, (ii) cell type-specific TFs are likely drivers of global TF binding patterns of shared TFs and (iii) cell type-specific binding of shared TFs actively contributes to cell type-specific gene expression.
A second mechanism that can contribute to cell type-specific binding of a ubiquitously expressed transcription factor is site availability.
NP cells expressed high levels of Gal-1 protein as compared to anulus fibrosus (AF) cells in immature tissues, while exogenous Gal-1 increased both NP and AF cell attachment to laminins and exhibited a similar binding to both cell types in vitro.
