Combinatorial motif analysis of regulatory gene expression in Mafb deficient macrophages

<p>Abstract</p> <p>Background</p> <p>Deficiency of the transcription factor MafB, which is normally expressed in macrophages, can underlie cellular dysfunction associated with a range of autoimmune diseases and arteriosclerosis. MafB has important roles in cell differentiation and regulation of target gene expression; however, the mechanisms of this regulation and the identities of other transcription factors with which MafB interacts remain uncertain. Bioinformatics methods provide a valuable approach for elucidating the nature of these interactions with transcriptional regulatory elements from a large number of DNA sequences. In particular, identification of patterns of co-occurrence of regulatory <it>cis</it>-elements (motifs) offers a robust approach.</p> <p>Results</p> <p>Here, the directional relationships among several functional motifs were evaluated using the Log-linear Graphical Model (LGM) after extraction and search for evolutionarily conserved motifs. This analysis highlighted GATA-1 motifs and 5’AT-rich half Maf recognition elements (MAREs) in promoter regions of 18 genes that were down-regulated in <it>Mafb</it> deficient macrophages. GATA-1 motifs and MafB motifs could regulate expression of these genes in both a negative and positive manner, respectively. The validity of this conclusion was tested with data from a luciferase assay that used a <it>C1qa</it> promoter construct carrying both the GATA-1 motifs and MAREs. GATA-1 was found to inhibit the activity of the <it>C1qa</it> promoter with the GATA-1 motifs and MafB motifs.</p> <p>Conclusions</p> <p>These observations suggest that both the GATA-1 motifs and MafB motifs are important for lineage specific expression of <it>C1qa</it>. In addition, these findings show that analysis of combinations of evolutionarily conserved motifs can be successfully used to identify patterns of gene regulation.</p

Combinatorial motif analysis of regulatory gene expression in Mafb deficient macrophages

Thesis (Ph. D. in Medical Sciences)--University of Tsukuba, (A), no. 5961, 2012.1.31Includes supplementary treatiseIncludes bibliographical reference