Assessing base-resolution DNA mechanics on the genome scale.

Intrinsic DNA properties including bending play a crucial role in diverse biological systems. A recent advance in a high-throughput technology called loop-seq makes it possible to determine the bendability of hundred thousand 50-bp DNA duplexes in one experiment. However, it's still challenging to assess base-resolution sequence bendability in large genomes such as human, which requires thousands of such experiments. Here, we introduce 'BendNet'-a deep neural network to predict the intrinsic DNA bending at base-resolution by using loop-seq results in yeast as training data. BendNet can predict the DNA bendability of any given sequence from different species with high accuracy. To explore the utility of BendNet, we applied it to the human genome and observed DNA bendability is associated with chromatin features and disease risk regions involving transcription/enhancer regulation, DNA replication, transcription factor binding and extrachromosomal circular DNA generation. These findings expand our understanding on DNA mechanics and its association with transcription regulation in mammals. Lastly, we built a comprehensive resource of genomic DNA bendability profiles for 307 species by applying BendNet, and provided an online tool to assess the bendability of user-specified DNA sequences (http://www.dnabendnet.com/).

RIIß-PKA in GABAergic Neurons of Dorsal Median Hypothalamus Governs White Adipose Browning.

The RIIß subunit of  cAMP-dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RIIß-knockout mice show leanness and increased UCP1 in brown adipose tissue. The authors have previously reported that RIIß reexpression in hypothalamic GABAergic neurons rescues the leanness. However, whether white adipose tissue (WAT) browning contributes to the leanness and whether RIIß-PKA in these neurons governs WAT browning are unknown. Here, this work reports that RIIß-KO mice exhibit a robust WAT browning. RIIß reexpression in dorsal median hypothalamic GABAergic neurons (DMH GABAergic neurons) abrogates WAT browning. Single-cell sequencing, transcriptome sequencing, and electrophysiological studies show increased GABAergic activity in DMH GABAergic neurons of RIIß-KO mice. Activation of DMH GABAergic neurons or inhibition of PKA in these neurons elicits WAT browning and thus lowers body weight. These findings reveal that RIIß-PKA in DMH GABAergic neurons regulates WAT browning. Targeting RIIß-PKA in DMH GABAergic neurons may offer a clinically useful way to promote WAT browning for treating obesity and other metabolic disorders.

Leptin signaling and leptin resistance.

With the prevalence of obesity and associated comorbidities, studies aimed at revealing mechanisms that regulate energy homeostasis have gained increasing interest. In 1994, the cloning of leptin was a milestone in metabolic research. As an adipocytokine, leptin governs food intake and energy homeostasis through leptin receptors (LepR) in the brain. The failure of increased leptin levels to suppress feeding and elevate energy expenditure is referred to as leptin resistance, which encompasses complex pathophysiological processes. Within the brain, LepR-expressing neurons are distributed in hypothalamus and other brain areas, and each population of the LepR-expressing neurons may mediate particular aspects of leptin effects. In LepR-expressing neurons, the binding of leptin to LepR initiates multiple signaling cascades including janus kinase (JAK)-signal transducers and activators of transcription (STAT) phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), extracellular regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, etc., mediating leptin actions. These findings place leptin at the intersection of metabolic and neuroendocrine regulations, and render leptin a key target for treating obesity and associated comorbidities. This review highlights the main discoveries that shaped the field of leptin for better understanding of the mechanism governing metabolic homeostasis, and guides the development of safe and effective interventions to treat obesity and associated diseases.