Repertoire of genetic control of gene expression in procaryotes

Writing 18 years ago, DR. STADLER pointed out that because of limitations in the knowledge and definition of the gene, questions about undetermined properties of the gene--the nature of the unit of reproduction, the unit of action of the "gene--string," the indivisible unit of the gene, the boundaries of a gene--were all still unanswerable. But these were the "all-important questions that we hope ultimately to answer by the ... development of new experimental operations."DAVID SCHLESSINGER, DEPARTMENT OF MICROBIOLOGY, WASHINGTON UNIVERSITY, ST. LOUIS, MISSOURI

Chromosomal bar codes produced by multicolor fluorescence in situ hybridization with multiple YAC clones and whole chromosome painting probes

Colored chromosome staining patterns, termed chromosomal ‘bar codes’ (CBCs), were obtained on human chromosomes by fluorescence in situ hybridization (FISH) with pools of Alu-PCR products from YAC dones containing human DNA inserts ranging from 100 kbp to 1 Mbp. In contrast to conventional G- or R-bands, the chromosomal position, extent, Individual color and relative signal intensity of each ‘bar’ could be modified depending on probe selection and labeling procedures. Alu-PCR amplification products were generated from 31 YAC clones which mapped to 37 different chromosome bands. For multiple color FISH, Alu-PCR amplification products from various clones were either biotinylated or labeled with digoxigenin. Probes from up to twenty YAC clones were used simultaneously to produce CBCs on selected human chromosomes. Evaluation using a cooled CCD camera and digital image analysis confirmed the high reproducibility of the bars from one metaphase spread to another. Combinatorial FISH with mixtures of whole chromosome paint probes was applied to paint seven chromosomes simultaneously in different colors along with a set of YAC clones which map to these chromosomes. We discuss the potential to construct analytical chromosomal bar codes adapted to particular needs of cytogenetic investigations and automated image analysis

Extremal Transitions and Five-Dimensional Supersymmetric Field Theories

We study five-dimensional supersymmetric field theories with one-dimensional Coulomb branch. We extend a previous analysis which led to non-trivial fixed points with $E_n$ symmetry ($E_8$, $E_7$, $E_6$, $E_5=Spin(10)$, $E_4=SU(5)$, $E_3=SU(3)\times SU(2)$, $E_2=SU(2)\times U(1)$ and $E_1=SU(2)$) by finding two new theories: $\tilde E_1$ with $U(1)$ symmetry and $E_0$ with no symmetry. The latter is a non-trivial theory with no relevant operators preserving the super-Poincar\'e symmetry. In terms of string theory these new field theories enable us to describe compactifications of the type I' theory on $S^1/Z_2$ with 16, 17 or 18 background D8-branes. These theories also play a crucial role in compactifications of M-theory on Calabi--Yau spaces, providing physical models for the contractions of del Pezzo surfaces to points (thereby completing the classification of singularities which can occur at codimension one in K\"ahler moduli). The structure of the Higgs branch yields a prediction which unifies the known mathematical facts about del Pezzo transitions in a quite remarkable way.Comment: 21 pages, 3 figures, minor change to appendi

Relative impact of indels versus SNPs on complex disease

It is unclear whether insertions and deletions (indels) are more likely to influence complex traits than abundant single‐nucleotide polymorphisms (SNPs). We sought to understand which category of variation is more likely to impact health. Using the SardiNIA study as an exemplar, we characterized 478,876 common indels and 8,246,244 common SNPs in up to 5,949 well‐phenotyped individuals from an isolated valley in Sardinia. We assessed association between 120 traits, resulting in 89 nonoverlapping‐associated loci.We evaluated whether indels were enriched among credible sets of potential causal variants. These credible sets included 1,319 SNPs and 88 indels. We did not find indels to be significantly enriched. Indels were the most likely causal variant in seven loci, including one locus associated with monocyte count where an indel with causality and mechanism previously demonstrated (rs200748895:TGCTG/T) had a 0.999 posterior probability. Overall, our results show a very modest and nonsignificant enrichment for common indels in associated loci.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/1/gepi22175_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/2/gepi22175-sup-0001-Gagliano-Supplementary.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/3/gepi22175.pd

The Forkhead Transcription Factor Foxl2 Is Sumoylated in Both Human and Mouse: Sumoylation Affects Its Stability, Localization, and Activity

The FOXL2 forkhead transcription factor is expressed in ovarian granulosa cells, and mutated FOXL2 causes the blepharophimosis, ptosis and epicanthus inversus syndrome (BPES) and predisposes to premature ovarian failure. Inactivation of Foxl2 in mice demonstrated its indispensability for female gonadal sex determination and ovary development and revealed its antagonism of Sox9, the effector of male testis development. To help to define the regulatory activities of FOXL2, we looked for interacting proteins. Based on yeast two-hybrid screening, we found that FOXL2 interacts with PIAS1 and UBC9, both parts of the sumoylation machinery. We showed that human FOXL2 is sumoylated in transfected cell lines, and that endogenous mouse Foxl2 is comparably sumoylated. This modification changes its cellular localization, stability and transcriptional activity. It is intriguing that similar sumoylation and regulatory consequences have also been reported for SOX9, the male counterpart of FOXL2 in somatic gonadal tissues

Lymphotoxin-β regulates periderm differentiation during embryonic skin development

Lymphotoxin-beta (LTbeta) is a key regulator of immune system development, but also affects late stages in hair development. In addition, high expression of LTbeta at an early stage in epidermis hinted at a further function in hair follicle induction or epithelial development. We report that hair follicles were normally induced in LTbeta(-/-) skin, but the periderm detached from the epidermis earlier, accompanied by premature appearance of keratohyalin granules. Expression profiling revealed dramatic down-regulation of a gene cluster encoding periderm-specific keratin-associated protein 13 and four novel paralogs in LTbeta(-/-) skin prior to periderm detachment. Epidermal differentiation markers, including small proline-rich proteins, filaggrins and several keratins, were also affected, but transiently in LTbeta(-/-) skin at the time of abnormal periderm detachment. As expected, Tabby mice, which lack the EDA gene, the putative upstream regulator of LTbeta in skin, showed similar though milder periderm histopathology and alterations in gene expression. Overall, LTbeta shows a primary early function in periderm differentiation, with later transient effects on epidermal and hair follicle differentiation

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms

ACKNOWLEDGMENTS. We thank Phillip B. Murray for help with the shRNA mapping pipeline and Francesc Lopez-Giraldez for help with RNAseq mapping software.Peer reviewedPostprintPostprin

Effects of aging and calorie restriction on the global gene expression profiles of mouse testis and ovary

<p>Abstract</p> <p>Background</p> <p>The aging of reproductive organs is not only a major social issue, but of special interest in aging research. A long-standing view of 'immortal germ line versus mortal soma' poses an important question of whether the reproductive tissues age in similar ways to the somatic tissues. As a first step to understand this phenomenon, we examine global changes in gene expression patterns by DNA microarrays in ovaries and testes of C57BL/6 mice at 1, 6, 16, and 24 months of age. In addition, we compared a group of mice on <it>ad libitum </it>(AL) feeding with a group on lifespan-extending 40% calorie restriction (CR).</p> <p>Results</p> <p>We found that gene expression changes occurred in aging gonads, but were generally different from those in somatic organs during aging. For example, only two functional categories of genes previously associated with aging in muscle, kidney, and brain were confirmed in ovary: genes associated with complement activation were upregulated, and genes associated with mitochondrial electron transport were downregulated. The bulk of the changes in gonads were mostly related to gonad-specific functions. Ovaries showed extensive gene expression changes with age, especially in the period when ovulation ceases (from 6 to 16 months), whereas testes showed only limited age-related changes. The same trend was seen for the effects of CR: CR-mediated reversal of age-associated gene expression changes, reported in somatic organs previously, was limited to a small number of genes in gonads. Instead, in both ovary and testis, CR caused small and mostly gonad-specific effects: suppression of ovulation in ovary and activation of testis-specific genes in testis.</p> <p>Conclusion</p> <p>Overall, the results are consistent with unique modes of aging and its modification by CR in testis and ovary.</p