The transcription factor Bcl11b/Ctip2 plays critical roles in the development of several systems and organs, including the immune system, central nervous system, skin and teeth. Here, we show that Bcl11b/Ctip2 is highly expressed in the developing vomeronasal system in mice and is required for its proper development. Bcl11b/Ctip2 is expressed in post-mitotic vomeronasal sensory neurons (VSNs) in the vomeronasal epithelium as well as projection neurons and GABAergic interneurons in the accessory olfactory bulb (AOB). In the absence of Bcl11b, these neurons are born in the correct number, but VSNs selectively die by apoptosis. The critical role of Bcl11b in vomeronasal system development is demonstrated by the abnormal phenotypes of Bcl11b-deficient mice: disorganization of layer formation of the AOB, impaired axonal projections of VSNs, a significant reduction in the expression of vomeronasal receptor genes, and defective mature differentiation of VSNs. VSNs can be classified into two major types of neurons, vomeronasal 1 receptor (V1r)/Gαi2-positive and vomeronasal 2 receptor (V2r)/Gαo-positive VSNs. We found that all Gαi2-positive cells co-expressed Gαo during embryogenesis. This co-expression is also observed in newly differentiated neurons in the adult VNE. Interestingly, loss of Bcl11b function resulted in an increased number of V1r/Gαi2-type VSNs and a decreased number of V2r/Gαo-type VSNs, suggesting that Bcl11b regulates the fate choice between these two VSN types. These results indicate that Bcl11b/Ctip2 is an essential regulator of the differentiation and dichotomy of VSNs.
BackgroundGene promoters in vertebrate genomes show distinct chromatin features such as stably positioned nucleosome array and DNA hypomethylation. The nucleosomes are known to have certain sequence preferences, and the prediction of nucleosome positioning from DNA sequence has been successful in some organisms such as yeast. However, at gene promoters where nucleosomes are much more stably positioned than in other regions, the sequence-based model has failed to work well, and sequence-independent mechanisms have been proposed.ResultsUsing DNase I-seq in medaka embryos, we demonstrated that hypomethylated domains (HMDs) specifically possess accessible nucleosome organization with longer linkers, and we reassessed the DNA sequence preference for nucleosome positioning in these specific regions. Remarkably, we found with a supervised machine learning algorithm, k-mer SVM, that nucleosome positioning in HMDs is accurately predictable from DNA sequence alone. Specific short sequences (6-mers) that contribute to the prediction are specifically enriched in HMDs and distribute periodically with approximately 200-bp intervals which prepattern the position of accessible linkers. Surprisingly, the sequence preference of the nucleosome and linker in HMDs is opposite from that reported previously. Furthermore, the periodicity of specific motifs at hypomethylated promoters was conserved in zebrafish.ConclusionThis study reveals strong link between nucleosome positioning and DNA sequence at vertebrate promoters, and we propose hypomethylated DNA-specific regulation of nucleosome positioning.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-017-0152-2) contains supplementary material, which is available to authorized users.
The genomes of vertebrates are globally methylated, but a small portion of genomic regions are known to be hypomethylated. Although hypomethylated domains (HMDs) have been implicated in transcriptional regulation in various ways, how a HMD is determined in a particular genomic region remains elusive. To search for DNA motifs essential for the formation of HMDs, we performed the genome-wide comparative analysis of genome and DNA methylation patterns of the two medaka inbred lines, Hd-rRII1 and HNI-II, which are derived from northern and southern subpopulations of Japan and exhibit high levels of genetic variations (SNP, ∼ 3%). We successfully mapped > 70% of HMDs in both genomes and found that the majority of those mapped HMDs are conserved between the two lines (common HMDs). Unexpectedly, the average genetic variations are similar in the common HMD and other genome regions. However, we identified short well-conserved motifs that are specifically enriched in HMDs, suggesting that they may play roles in the establishment of HMDs in the medaka genome.
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