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Developmentally regulated transcription of the four liver-specific genes for inter-alpha-inhibitor family in mouse.

ABSTRACT: The inter-alpha-inhibitor family is composed of the plasma-protease inhibitors inter-alpha-inhibitor, pre-alpha-inhibitor and bikunin. Inter-alpha-inhibitor and pre-alpha-inhibitor are distinct assemblies of bikunin with distinct sets from three heavy (H) chains designated H1, H2 and H3. These H chains are encoded by a set of three evolutionarily related H genes, and bikunin by an alpha-1-microglobulin/bikunin precursor gene (AMBP). This precursor is cleaved to yield bikunin, a member of the Kunitz-type protease-inhibitor superfamily, and alpha-1-microglobulin, which belongs to the lipocalin superfamily. Northern-blot experiments with RNAs obtained from various tissues in fetal and in adult mice indicated that the transcription of the four AMBP and H genes is liver-restricted, although there is expression of H3 in brain. An analysis of the H1, H2, H3 and AMBP transcripts, as well as of transcripts for other control genes, in liver during development showed a progressive increase in the amounts of the H1, H2, H3 and AMBP RNAs, which all peak transiently at day 5 after birth. This was shown by a nuclear run-on experiment to originate from a change in transcription rate. The transient and postnatal increase in transcription could be explained neither by the liver-restricted expression nor by a common origin of these four genes, nor by a perinatal requirement for many lipocalins or protease inhibitors. This suggests that all four genes are perinatally triggered at the level of similar elements in their transcriptional regulatory regions, a conclusion strengthened by the weak expression of the four genes that is seen in a mutant mouse strain (albino) that is deficient in some liver-specific transcription factors.

SUBMITTER: Salier JP

PROVIDER: S-EPMC1137658 | biostudies-other | 1993 Nov

REPOSITORIES: biostudies-other

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Project description:BackgroundMyxococcus xanthus is a bacterium that undergoes multicellular development when starved. Cells move to aggregation centers and form fruiting bodies in which cells differentiate into dormant spores. MrpC appears to directly activate transcription of fruA, which also codes for a transcription factor. Both MrpC and FruA are crucial for aggregation and sporulation. The two proteins bind cooperatively in promoter regions of some developmental genes.ResultsChromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) and bioinformatic analysis of cells that had formed nascent fruiting bodies revealed 1608 putative MrpC binding sites. These sites included several known to bind MrpC and they were preferentially distributed in likely promoter regions, especially those of genes up-regulated during development. The up-regulated genes include 22 coding for protein kinases. Some of these are known to be directly involved in fruiting body formation and several negatively regulate MrpC accumulation. Our results also implicate MrpC as a direct activator or repressor of genes coding for several transcription factors known to be important for development, for a major spore protein and several proteins important for spore formation, for proteins involved in extracellular A- and C-signaling, and intracellular ppGpp-signaling during development, and for proteins that control the fate of other proteins or play a role in motility. We found that the putative MrpC binding sites revealed by ChIP-seq are enriched for DNA sequences that strongly resemble a consensus sequence for MrpC binding proposed previously. MrpC2, an N-terminally truncated form of MrpC, bound to DNA sequences matching the consensus in all 11 cases tested. Using longer DNA segments containing 15 of the putative MrpC binding sites from our ChIP-seq analysis as probes in electrophoretic mobility shift assays, evidence for one or more MrpC2 binding site was observed in all cases and evidence for cooperative binding of MrpC2 and FruA was seen in 13 cases.ConclusionsWe conclude that MrpC and MrpC2 bind to promoter regions of hundreds of developmentally-regulated genes in M. xanthus, in many cases cooperatively with FruA. This binding very likely up-regulates protein kinases, and up- or down-regulates other proteins that profoundly influence the developmental process.

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Developmentally regulated transcription of the four liver-specific genes for inter-alpha-inhibitor family in mouse.

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