Cell Rep Med.: auth.: group Reymond

Cell Rep Med. 2023 Aug 15;4(8):101155.
doi: 10.1016/j.xcrm.2023.101155.

Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease

Ruth Hanssen 1Chiara Auwerx 2Maarja Jõeloo 3Marie C Sadler 4Estonian Biobank Research Team 5Elana Henning 1Julia Keogh 1Rebecca Bounds 1Miriam Smith 1Helen V Firth 6Zoltán Kutalik 4I Sadaf Farooqi 7Alexandre Reymond 8Katherine Lawler 9

Abstract

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.: co-auth.: group Vastenhouw

Biol Open. 2023 May 15;12(5):bio059783.

 doi: 10.1242/bio.059783. Epub 2023 May 17.

Actin filaments accumulated in the nucleus remain in the vicinity of condensing chromosomes in the zebrafish early embryo

Haruka Oda 1Yuko Sato 1Shigehiro A Kawashima 2Yusuke Fujiwara 2Máté Pálfy 3Edlyn Wu 3 4Nadine L Vastenhouw 3 4Motomu Kanai 2Hiroshi Kimura 1

Abstract

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.: auth.: group Vastenhouw

Nature. 2023 Jul 17.

 doi: 10.1038/d41586-023-01618-5. Online ahead of print.

Sleeping embryonic genomes are awoken by OBOX proteins

Edlyn WuNadine 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.: co-auth.: C.Fankhauser

Trends Plant Sci. 2023 Aug 11;S1360-1385(23)00232-7.

 doi: 10.1016/j.tplants.2023.07.001. Online ahead of print.

25 Years of thermomorphogenesis research: milestones and perspectives

Marcel Quint 1Carolin Delker 2Sureshkumar Balasubramanian 3Martin Balcerowicz 4Jorge J Casal 5Christian Danve M Castroverde 6Meng Chen 7Xuemei Chen 8Ive De Smet 9Christian Fankhauser 10Keara A Franklin 11Karen J Halliday 12Scott Hayes 13Danhua Jiang 14Jae-Hoon Jung 15Eirini Kaiserli 16S Vinod Kumar 17Daniel Maag 18Eunkyoo Oh 19Chung-Mo Park 20Steven Penfield 21Giorgio Perrella 22Salomé Prat 23Rodrigo S Reis 24Philip A Wigge 25Björn C Willige 26Martijn van Zanten 27

Abstract

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.: auth.: group Gambetta

Cell. 2023 Jul 25;S0092-8674(23)00741-9.

 doi: 10.1016/j.cell.2023.07.008. Online ahead of print.

Chromosome-level organization of the regulatory genome in the Drosophila nervous system

Giriram Mohana 1Julien Dorier 2Xiao Li 3Marion Mouginot 1Rebecca C Smith 4Héléna Malek 1Marion Leleu 2Daniel Rodriguez 1Jenisha Khadka 1Patrycja Rosa 5Pascal Cousin 1Christian Iseli 2Simon Restrepo 6Nicolas Guex 2Brian D McCabe 4Aleksander Jankowski 7Michael S Levine 8Maria Cristina Gambetta 9

Abstract

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.: auth.: group Thorens

EMBO Rep. 2023 Jun 14;e57344.

 doi: 10.15252/embr.202357344. Online ahead of print.

Tmem117 in AVP neurons regulates the counterregulatory response to hypoglycemia

Sevasti Gaspari 1Gwenaël Labouèbe 1Alexandre Picard 1Xavier Berney 1Ana Rodriguez Sanchez-Archidona 1Bernard Thorens 1

Abstract

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.