Cell Rep Med. 2023 Aug 15;4(8):101155.
Ruth Hanssen 1, Chiara Auwerx 2, Maarja Jõeloo 3, Marie C Sadler 4; Estonian Biobank Research Team 5; Elana Henning 1, Julia Keogh 1, Rebecca Bounds 1, Miriam Smith 1, Helen V Firth 6, Zoltán Kutalik 4, I Sadaf Farooqi 7, Alexandre Reymond 8, Katherine Lawler 9
New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10-10) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p = 8.1 × 10-6). We conclude that people with 16p11.2 BP2-3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling.
Biol Open. 2023 May 15;12(5):bio059783.
doi: 10.1242/bio.059783. Epub 2023 May 17.
Haruka Oda 1, Yuko Sato 1, Shigehiro A Kawashima 2, Yusuke Fujiwara 2, Máté Pálfy 3, Edlyn Wu 3 4, Nadine L Vastenhouw 3 4, Motomu Kanai 2, Hiroshi Kimura 1
In the cytoplasm, filamentous actin (F-actin) plays a critical role in cell regulation, including cell migration, stress fiber formation, and cytokinesis. Recent studies have shown that actin filaments that form in the nucleus are associated with diverse functions. Here, using live imaging of an F-actin-specific probe, superfolder GFP-tagged utrophin (UtrCH-sfGFP), we demonstrated the dynamics of nuclear actin in zebrafish (Danio rerio) embryos. In early zebrafish embryos up to around the high stage, UtrCH-sfGFP increasingly accumulated in nuclei during the interphase and reached a peak during the prophase. After nuclear envelope breakdown (NEBD), patches of UtrCH-sfGFP remained in the vicinity of condensing chromosomes during the prometaphase to metaphase. When zygotic transcription was inhibited by injecting α-amanitin, the nuclear accumulation of UtrCH-sfGFP was still observed at the sphere and dome stages, suggesting that zygotic transcription may induce a decrease in nuclear F-actin. The accumulation of F-actin in nuclei may contribute to proper mitotic progression of large cells with rapid cell cycles in zebrafish early embryos, by assisting in NEBD, chromosome congression, and/or spindle assembly.
Nature. 2023 Jul 17.
doi: 10.1038/d41586-023-01618-5. Online ahead of print.
Edlyn Wu, Nadine L Vastenhouw
Activation of gene transcription is precisely regulated in early embryos. The identification of key transcription factors now shows how the transcription machinery is guided to the right place at the right time in mice.
Keywords: Developmental biology; Molecular biology.
Trends Plant Sci. 2023 Aug 11;S1360-1385(23)00232-7.
doi: 10.1016/j.tplants.2023.07.001. Online ahead of print.
Marcel Quint 1, Carolin Delker 2, Sureshkumar Balasubramanian 3, Martin Balcerowicz 4, Jorge J Casal 5, Christian Danve M Castroverde 6, Meng Chen 7, Xuemei Chen 8, Ive De Smet 9, Christian Fankhauser 10, Keara A Franklin 11, Karen J Halliday 12, Scott Hayes 13, Danhua Jiang 14, Jae-Hoon Jung 15, Eirini Kaiserli 16, S Vinod Kumar 17, Daniel Maag 18, Eunkyoo Oh 19, Chung-Mo Park 20, Steven Penfield 21, Giorgio Perrella 22, Salomé Prat 23, Rodrigo S Reis 24, Philip A Wigge 25, Björn C Willige 26, Martijn van Zanten 27
In 1998, Bill Gray and colleagues showed that warm temperatures trigger arabidopsis hypocotyl elongation in an auxin-dependent manner. This laid the foundation for a vibrant research discipline. With several active members of the ‘thermomorphogenesis’ community, we here reflect on 25 years of elevated ambient temperature research and look to the future.
Keywords: high temperature signalling; hypocotyl; phytohormones; thermomorphogenesis; thermosensor.
Cell. 2023 Jul 25;S0092-8674(23)00741-9.
doi: 10.1016/j.cell.2023.07.008. Online ahead of print.
Giriram Mohana 1, Julien Dorier 2, Xiao Li 3, Marion Mouginot 1, Rebecca C Smith 4, Héléna Malek 1, Marion Leleu 2, Daniel Rodriguez 1, Jenisha Khadka 1, Patrycja Rosa 5, Pascal Cousin 1, Christian Iseli 2, Simon Restrepo 6, Nicolas Guex 2, Brian D McCabe 4, Aleksander Jankowski 7, Michael S Levine 8, Maria Cristina Gambetta 9
Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations.
Keywords: Drosophila; TAD; chromosomal loop; gene regulation; genome architecture; genome organization; nervous system; neuron; transcription.
EMBO Rep. 2023 Jun 14;e57344.
doi: 10.15252/embr.202357344. Online ahead of print.
Sevasti Gaspari 1, Gwenaël Labouèbe 1, Alexandre Picard 1, Xavier Berney 1, Ana Rodriguez Sanchez-Archidona 1, Bernard Thorens 1
The counterregulatory response to hypoglycemia (CRR), which ensures a sufficient glucose supply to the brain, is an essential survival function. It is orchestrated by incompletely characterized glucose-sensing neurons, which trigger a coordinated autonomous and hormonal response that restores normoglycemia. Here, we investigate the role of hypothalamic Tmem117, identified in a genetic screen as a regulator of CRR. We show that Tmem117 is expressed in vasopressin magnocellular neurons of the hypothalamus. Tmem117 inactivation in these neurons increases hypoglycemia-induced vasopressin secretion leading to higher glucagon secretion in male mice, and this effect is estrus cycle phase dependent in female mice. Ex vivo electrophysiological analysis, in situ hybridization, and in vivo calcium imaging reveal that Tmem117 inactivation does not affect the glucose-sensing properties of vasopressin neurons but increases ER stress, ROS production, and intracellular calcium levels accompanied by increased vasopressin production and secretion. Thus, Tmem117 in vasopressin neurons is a physiological regulator of glucagon secretion, which highlights the role of these neurons in the coordinated response to hypoglycemia.