Borders of Cis-Regulatory DNA Sequences Preferentially Harbor the Divergent Transcription Factor Binding Motifs in the Human Genome

Changes in cis-regulatory DNA sequences and transcription factor (TF) repertoires provide major sources of phenotypic diversity that shape the evolution of gene regulation in eukaryotes. The DNA-binding specificities of TFs may be diversified or produce new variants in different eukaryotic species. However, it is currently unclear how various levels of divergence in TF DNA-binding specificities or motifs became introduced into the cis-regulatory DNA regions of the genome over evolutionary time. Here, we first estimated the evolutionary divergence levels of TF binding motifs and quantified their occurrence at DNase I-hypersensitive sites. Results from our in silico motif scan and experimentally derived chromatin immunoprecipitation (TF-ChIP) show that the divergent motifs tend to be introduced in the edges of cis-regulatory regions, which is probably accompanied by the expansion of the accessible core of promoter-associated regulatory elements during evolution. We also find that the genes neighboring the expanded cis-regulatory regions with the most divergent motifs are associated with functions like development and morphogenesis. Accordingly, we propose that the accumulation of divergent motifs in the edges of cis-regulatory regions provides a functional mechanism for the evolution of divergent regulatory circuits

Impact of DNA-binding position variants on yeast gene expression

Transcription factors (TFs) regulate gene expression by binding to specific binding sites (TFBSs) in gene promoters. TFBS motifs may contain one or more variable positions. Although the prevailing assumption is that nucleotide variants at such positions are functionally equivalent, there is increasing evidence that such variants play a role in regulation of gene expression. In this article, we propose a method for studying the relationship between the expression of target genes and nucleotide variants in TFBS motifs at a genome-wide scale in Saccharomyces cerevisiae, especially the combinatorial effects of variants at two positions. Our analysis shows that nucleotide variations in more than one-third of variable positions and in 20% of dependent position pairs are highly correlated to gene expression. We define such positions as ‘functional’. However, some positions are only functional as dependent pairs, but not individually. In addition, a significant proportion of the functional positions have been well conserved across all yeast-related species studied. We also find that some positions require the presence of co-occurring TFs, while others maintain their functionality in the absence of a co-occurring TF. Our analysis supports the importance of nucleotide variants at variable positions of TFBSs in gene regulation

Magnetotransport in an aluminum thin film on a GaAs substrate grown by molecular beam epitaxy

Magnetotransport measurements are performed on an aluminum thin film grown on a GaAs substrate. A crossover from electron- to hole-dominant transport can be inferred from both longitudinal resistivity and Hall resistivity with increasing the perpendicular magnetic field B. Also, phenomena of localization effects can be seen at low B. By analyzing the zero-field resistivity as a function of temperature T, we show the importance of surface scattering in such a nanoscale film

Genome-Wide Association Study of Young-Onset Hypertension in the Han Chinese Population of Taiwan

Young-onset hypertension has a stronger genetic component than late-onset counterpart; thus, the identification of genes related to its susceptibility is a critical issue for the prevention and management of this disease. We carried out a two-stage association scan to map young-onset hypertension susceptibility genes. The first-stage analysis, a genome-wide association study, analyzed 175 matched case-control pairs; the second-stage analysis, a confirmatory association study, verified the results at the first stage based on a total of 1,008 patients and 1,008 controls. Single-locus association tests, multilocus association tests and pair-wise gene-gene interaction tests were performed to identify young-onset hypertension susceptibility genes. After considering stringent adjustments of multiple testing, gene annotation and single-nucleotide polymorphism (SNP) quality, four SNPs from two SNP triplets with strong association signals (−log10(p)>7) and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (−log10(p)>8) were carefully re-examined. The confirmatory study verified the association for a SNP quartet 219 kb and 495 kb downstream of LOC344371 (a hypothetical gene) and RASGRP3 on chromosome 2p22.3, respectively. The latter has been implicated in the abnormal vascular responsiveness to endothelin-1 and angiotensin II in diabetic-hypertensive rats. Intrinsic synergy involving IMPG1 on chromosome 6q14.2-q15 was also verified. IMPG1 encodes interphotoreceptor matrix proteoglycan 1 which has cation binding capacity. The genes are novel hypertension targets identified in this first genome-wide hypertension association study of the Han Chinese population