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Neil O Robertson, Ngaio C Smith, Athina Manakas, Mahiar Mahjoub, Gordon McDonald, Ann H Kwan, Jacqueline M Matthews
Intrinsically disordered regions are highly represented among mammalian transcription factors, where they often contribute to the formation of multiprotein complexes that regulate gene expression. An example of this occurs with LIM-homeodomain (LIM-HD) proteins in the developing spinal cord. The LIM-HD protein LHX3 and the LIM-HD cofactor LDB1 form a binary complex that gives rise to interneurons, whereas in adjacent cell populations, LHX3 and LDB1 form a rearranged ternary complex with the LIM-HD protein ISL1, resulting in motor neurons...
April 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Morteza Seifi, Michael A Walter
Mutations in PITX2 have been implicated in several genetic disorders, particularly Axenfeld-Rieger syndrome. In order to determine the most reliable bioinformatics tools to assess the likely pathogenicity of PITX2 variants, the results of bioinformatics predictions were compared to the impact of variants on PITX2 structure and function. The MutPred, Provean, and PMUT bioinformatic tools were found to have the highest performance in predicting the pathogenicity effects of all 18 characterized missense variants in PITX2, all with sensitivity and specificity >93%...
2018: PloS One
Jamie M Baird-Titus, Mahendra Thapa, Thomas Doerdelmann, Kelly A Combs, Mark Rance
An important but poorly characterized contribution to the thermodynamics of protein-DNA interactions is the loss of entropy that occurs from restricting the conformational freedom of amino acid side chains. The effect of restricting the flexibility of several side chains at a protein-DNA interface may be comparable in many cases to the other factors that determine the binding thermodynamics, and may therefore play a key role in dictating the binding affinity and/or specificity. Because the entropic contributions, including the presence and influence of side-chain dynamics, are especially difficult to estimate based on structural information, it is important to pursue experimental and theoretical studies that can provide direct information regarding these issues...
April 17, 2018: Biochemistry
Stephen A Snipes, Kevin Rodriguez, Aaron E DeVries, Kaori N Miyawaki, Mariano Perales, Mingtang Xie, G Venugopala Reddy
Concentration-dependent transcriptional regulation and the spatial regulation of transcription factor levels are poorly studied in plant development. WUSCHEL, a stem cell-promoting homeodomain transcription factor, accumulates at a higher level in the rib meristem than in the overlying central zone, which harbors stem cells in the shoot apical meristems of Arabidopsis thaliana. The differential accumulation of WUSCHEL in adjacent cells is critical for the spatial regulation and levels of CLAVATA3, a negative regulator of WUSCHEL transcription...
April 16, 2018: PLoS Genetics
Lanhuan Meng, Zhongqi Fan, Qiang Zhang, Cuicui Wang, Ying Gao, Yikang Deng, Benzhong Zhu, Hongliang Zhu, Chen Jianye, Wei Shan, Xunren Yin, Silin Zhong, Donald Grierson, Cai-Zhong Jiang, Yunbo Luo, Da-Qi Fu
Chloroplast development and chlorophyll(Chl)metabolism in unripe tomato contribute to the growth and quality of the fruit. However, the mechanism is poorly understood. In this work, we initially studied seven homeobox-containing transcription factors (TFs) with specific ripening-associated expression patterns by virus-induced gene silencing (VIGS) technology and found that inhibiting the expression of one of these TFs, BEL1-LIKE HOMEODOMAIN11 (SlBEL11), significantly increased Chl levels in unripe tomato fruit...
April 16, 2018: Plant Journal: for Cell and Molecular Biology
Jimmy de Melo, Brian S Clark, Anand Venkataraman, Fion Shiau, Cristina Zibetti, Seth Blackshaw
Precise control of the relative ratio of retinal neurons and glia generated during development is essential for visual function. We show that Lhx2 , which encodes a LIM-homeodomain transcription factor essential for specification and differentiation of retinal Müller glia, also plays a critical role in the development of retinal neurons. Overexpression of Lhx2 with its transcriptional coactivator Ldb1 , triggers cell cycle exit and inhibits both Notch signaling and retinal gliogenesis. Lhx2/Ldb1 overexpression also induced the formation of wide-field amacrine cells (wfACs)...
April 12, 2018: Development
S Scofield, A Murison, A Jones, J Fozard, M Aida, L R Band, M Bennett, J A H Murray
The Arabidopsis homeodomain transcription factor SHOOT MERISTEMLESS (STM) is critical for shoot apical meristem (SAM) function, yet the components and structure of the STM gene regulatory network (GRN) are largely unknown. Here we show that transcriptional regulators are overrepresented amongst STM-regulated genes, and using these as GRN components in Bayesian network analysis we infer STM GRN associations and reveal regulatory relationships between STM and factors involved in multiple aspects of SAM function, including hormone regulation, TCP-mediated control of cell differentiation, AIL/PLT-mediated regulation of pluripotency and phyllotaxis, and specification of meristem-organ boundary zones via CUC1...
April 12, 2018: Development
Hiroaki Mitsuhashi, Satoshi Ishimaru, Sachiko Homma, Bryant Yu, Yuki Honma, Mary Lou Beermann, Jeffrey Boone Miller
Aberrant expression of the full-length isoform of DUX4 (DUX4-FL) appears to underlie pathogenesis in facioscapulohumeral muscular dystrophy (FSHD). DUX4-FL is a transcription factor and ectopic expression of DUX4-FL is toxic to most cells. Previous studies showed that DUX4-FL-induced pathology requires intact homeodomains and that transcriptional activation required the C-terminal region. In this study, we further examined the functional domains of DUX4 by generating mutant, deletion, and fusion variants of DUX4...
April 4, 2018: Biology Open
Hiromasa Tabata, Akihiro Koinui, Atsushi Ogura, Daisuke Nishihara, Hiroaki Yamamoto
Paired box (Pax) 6, a member of the Pax family of transcription factors, contains two DNA-binding domains, called the paired domain (PD) and the homeodomain (HD), and plays pivotal roles in development of structures such as the eye, central nervous system and pancreas. Pax6 is a major developmental switching molecule because, for example, ectopic expression of the Pax6 gene can induce ectopic whole eye development. Intensive research has been devoted to elucidating the molecular mechanism(s) involved in the function(s) of Pax6, but many issues remain unexplained...
April 2, 2018: Genes & Genetic Systems
Ningfei An, Saira Khan, Molly K Imgruet, Sandeep K Gurbuxani, Stephanie N Konecki, Michael R Burgess, Megan E McNerney
Monosomy 7 (-7) and del(7q) are high-risk cytogenetic abnormalities common in myeloid malignancies. We previously reported that CUX1 , a homeodomain-containing transcription factor encoded on 7q22, is frequently inactivated in myeloid neoplasms, and CUX1 myeloid tumor suppressor activity is conserved from humans to Drosophila CUX1 inactivating mutations are recurrent in clonal hematopoiesis of indeterminate potential (CHIP) as well as myeloid malignancies, in which they independently carry a poor prognosis...
March 28, 2018: Blood
Erica C Pandolfi, Hanne M Hoffmann, Erica L Schoeller, Michael R Gorman, Pamela L Mellon
Mating behavior in males and females is dependent on olfactory cues processed through both the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). Signaling through the MOE is critical for the initiation of male mating behavior, and the loss of MOE signaling severely compromises this comportment. Here, we demonstrate that dosage of the homeodomain gene Six3 affects the degree of development of MOE but not the VNO. Anomalous MOE development in Six3 heterozygote mice leads to hyposmia, specifically disrupting male mounting behavior by impairing detection of volatile female estrus pheromones...
March 27, 2018: Molecular Neurobiology
Chong Hu, Yafen Zhu, Yanwei Cui, Kaili Cheng, Wan Liang, Zhuoyun Wei, Mingsong Zhu, Hongju Yin, Li Zeng, Ya Xiao, Minghui Lv, Jing Yi, Suiwen Hou, Kai He, Jia Li, Xiaoping Gou
Continuous organ initiation and outgrowth in plants relies on the proliferation and differentiation of stem cells maintained by the CLAVATA (CLV)-WUSCHEL (WUS) negative-feedback loop1-3 . Leucine-rich repeat receptor-like protein kinases (LRR-RLKs), including CLV1, BARELY ANY MERISTEMS and RECEPTOR-LIKE PROTEIN KINASE 2 (RPK2), a receptor-like protein CLV2 and a pseudokinase CORYNE (CRN) are involved in the perception of the CLV3 signal to repress WUS expression4-10 . WUS, a homeodomain transcription factor, in turn directly activates CLV3 expression and promotes stem cell activity in the shoot apical meristem11,12 ...
April 2018: Nature Plants
Subhash Kairamkonda, Upendra Nongthomba
LIM domain, constituted by two tandem C2H2 zinc finger motif, proteins regulate several biological processes. They are usually found associated with various functional domains like Homeodomain, kinase domain and other protein binding domains. LIM proteins that are devoid of other domains are called LIM only proteins (LMO). LMO proteins were first identified in humans and are implicated in development and oncogenesis. They regulate various cell specifications by regulating the activity of respective transcriptional complexes...
March 23, 2018: Experimental Cell Research
Alexander Semaan, Barbara Uhl, Vittorio Branchi, Philipp Lingohr, Friedrich Bootz, Glen Kristiansen, Jörg C Kalff, Hanno Matthaei, Dimitrios Pantelis, Dimo Dietrich
BACKGROUND: New treatment modalities and a growing understanding of the complex genetic tumor landscape have improved the outcome of colorectal cancer (CRC) patients. Nonetheless, more individualized treatment regimens, taking individual tumor characteristics into account, have been recently postulated and prognostic biomarkers are needed. We therefore evaluated the prognostic potential of paired-like homeodomain transcription factor 2 (PITX2) promoter methylation in CRC patients. MATERIALS AND METHODS: Data of 2 independent cohorts were investigated...
February 23, 2018: Clinical Colorectal Cancer
Paul Brennan, David Bowkett, Romain Talon, Cynthia Tallant, Chris Schofield, Gordon Bruton, Frank von Delft, Stefan Knapp
Epigenetics is of rapidly growing field in drug discovery. Of particular interest is the role of post-translational modifications to histone and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains, is that with the notable exception of bromodomains, they tend not to possess a well enclosed binding site amenable to small molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains there are opportunities for designing inhibitors that bind at a domain-domain interface which provide a more suitable interaction pocket...
March 26, 2018: ChemMedChem
Simona Monterisi, Pietro Lo Riso, Karin Russo, Giovanni Bertalot, Manuela Vecchi, Giuseppe Testa, Pier Paolo Di Fiore, Fabrizio Bianchi
HOXB7 is a homeodomain (HOX) transcription factor involved in regional body patterning of invertebrates and vertebrates. We previously identified HOXB7 within a ten-gene prognostic signature for lung adenocarcinoma, where increased expression of HOXB7 was associated with poor prognosis. This raises the question of how HOXB7 overexpression can influence the metastatic behavior of lung adenocarcinoma. Here, we analyzed publicly available microarray and RNA-seq lung cancer expression datasets and found that HOXB7-overexpressing tumors are enriched in gene signatures characterizing adult and embryonic stem cells (SC), and induced pluripotent stem cells (iPSC)...
March 26, 2018: Oncogene
Yanqing Xiao, Yanli Chen, Yanpeng Ding, Jie Wu, Peng Wang, Ya Yu, Xi Wei, Ye Wang, Chaojun Zhang, Fuguang Li, Xiaoyang Ge
The WUSCHEL (WUS) gene encodes a plant-specific homeodomain-containing transcriptional regulator, which plays important roles during embryogenesis, as well as in the formation of shoot and flower meristems. Here, we isolated two homologues of Arabidopsis thaliana WUS (AtWUS), GhWUS1a_At and GhWUS1b_At, from upland cotton (Gossypium hirsutum). Domain analysis suggested that the two putative GhWUS proteins contained a highly conserved DNA-binding HOX domain and a WUS-box. Expression profile analysis showed that GhWUSs were predominantly expressed during the embryoid stage...
May 2018: Plant Science: An International Journal of Experimental Plant Biology
Jia Wang, Jingfei Chen, Jingwen Li, Liaoyuan An, Yefei Wang, Qingshan Huang, Lishan Yao
A combined experimental and computational study is performed for arginine side chain stacking with the protein α-helix. Theremostability measurements of Aristaless homeodomain, a helical protein, suggest that mutating the arginine residue R106, R137 or R141, which has the guanidino side chain stacking with the peptide plane, to alanine, destabilizes the protein. The R-PP stacking has an energy of ∼0.2-0.4 kcal/mol. This stacking interaction mainly comes from dispersion and electrostatics, based on MP2 calculations with the energy decomposition analysis...
March 25, 2018: Proteins
Jayanna N Banavath, Thammineni Chakradhar, Varakumar Pandit, Sravani Konduru, Krishna K Guduru, Chandra S Akila, Sudhakar Podha, Chandra O R Puli
Peanut is an important oilseed and food legume cultivated as a rain-fed crop in semi-arid tropics. Drought and high salinity are the major abiotic stresses limiting the peanut productivity in this region. Development of drought and salt tolerant peanut varieties with improved yield potential using biotechnological approach is highly desirable to improve the peanut productivity in marginal geographies. As abiotic stress tolerance and yield represent complex traits, engineering of regulatory genes to produce abiotic stress-resilient transgenic crops appears to be a viable approach...
2018: Frontiers in Chemistry
Yi-Mei J Lin, I-Lun Hsin, H Sunny Sun, Shankung Lin, Yen-Ling Lai, Hsuan-Ying Chen, Ting-Yu Chen, Ya-Ping Chen, Yi-Ting Shen, Hung-Ming Wu
POU-homeodomain transcription factor POU3F2 is a critical transcription factor that participates in neuronal differentiation. However, little is known about its downstream mediators. Here genome-wide analyses of a human neuronal differentiation cell model, NT2D1, suggested neurotrophin-3 (NTF3), a key mediator of neuronal development during the early neurogenic period, as a putative regulatory target of POU3F2. Western blot, cDNA microarray, and real-time quantitative PCR analyses showed that POU3F2 and NTF3 were upregulated during neuronal differentiation...
March 16, 2018: Molecular Neurobiology
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