Biology subjects

Robinson, E. L.

Publications and source records attributed to Robinson, E. L..

5 recordsLinked to original sources

bioRxiv2023

HDAC11 inhibition triggers bimodal thermogenic pathways to circumvent adipocyte catecholamine resistance

Stimulation of adipocyte {beta}-adrenergic receptors ({beta}-ARs) induces expression of uncoupling protein 1 (UCP1), promoting non-shivering thermogenesis. Association of {beta}-ARs with a lysine myristoylated form of A-kinase anchoring protein 12 (AKAP12)/gravin- is required for downstream signaling that culminates in UCP1 induction. Conversely, demyristoylation of gravin- by histone deacetylase 11 (HDAC11) suppresses this pathway. Whether inhibition of HDAC11 in adipocytes is sufficient to drive UCP1 expression independently of {beta}-ARs is not known. Here, we demonstrate that adipocyte-specific deletion of HDAC11 in mice leads to robust induction of UCP1 in adipose tissue (AT), resulting in increased body temperature. These effects are mimicked by treating mice in vivo or human AT ex vivo with an HDAC11-selective inhibitor, FT895. FT895 triggers biphasic, gravin- myristoylation-dependent induction of UCP1 protein expression, with a non-canonical acute response that is post-transcriptional and independent of protein kinase A (PKA), and a delayed response requiring PKA activity and new Ucp1 mRNA synthesis. Remarkably, HDAC11 inhibition promotes UCP1 expression even in models of adipocyte catecholamine resistance where {beta}-AR signaling is blocked. These findings define cell autonomous, multi-modal roles for HDAC11 as a suppressor of thermogenesis, and highlight the potential of inhibiting HDAC11 to therapeutically alter AT phenotype independently of {beta}-AR stimulation.

molecular biology↗

bioRxiv2021

Human embryonic stem cell-derived cardiomyocytes express SARS-CoV-2 host entry proteins: screen to identify inhibitors of infection

Patients with cardiovascular comorbidities are more susceptible to severe infection with SARS-CoV-2, known to directly cause pathological damage to cardiovascular tissue. We outline a screening platform using human embryonic stem cell-derived cardiomyocytes, confirmed to express the protein machinery critical for SARS-CoV-2 infection, and a pseudotyped virus system. The method has allowed us to identify benztropine and DX600 as novel inhibitors of SARS-CoV-2 infection.

pharmacology and toxicology↗

bioRxiv2020

MSK phosphorylation of H3S28 is required for immediate early gene induction and cardiac hypertrophy

Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not yet resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the Mitogen and Stress activated protein Kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights and highlight the role of signalling to the epigenome in gene expression regulation during cardiac hypertrophy. Brief summary one sentenceMSK1/2 phosphorylation of Histone 3 Serine 28 couples MAPK signalling with chromatin remodelling and immediate early gene expression to induce pro-hypertrophic cardiac transcriptional responses.

molecular biology↗

bioRxiv2020

Genes Encoding ACE2, TMPRSS2 and Related Proteins Mediating SARS-CoV-2 Viral Entry are Upregulated with Age in Human Cardiomyocytes

Age is an independent risk factor for adverse outcome in patients following COVID-19 infection. We hypothesised that differential expression of genes encoding proteins proposed to be required for entry of SARS-Cov-2 in aged compared to younger cardiomyocytes might contribute to the susceptibility of older individuals to COVID-19-associated cardiovascular complications.We generated strand-specific RNA-sequencing libraries from RNA isolated from flow-sorted cardiomyocyte nuclei from left ventricular tissue. RNASeq data were compared between five young (19-25yr) and five older (63-78yr) Caucasian males who had not been on medication or exhibited evidence of cardiovascular disease post-mortem.Expression of relevant genes encoding ACE2, TMPRSS2, TMPRS11D, TMPRS11E, FURIN, CTSL, CTSB and B0AT1/SLC6A19 were upregulated in aged cardiomyocytes and the combined relative cardiomyocyte expression of these genes correlated positively with age. Genes encoding proteins in the RAAS and interferon/interleukin pathways were also upregulated such as ACE, AGTR1, MAS1 and IL6R.Our results highlight SARS-CoV-2 related genes that have higher expression in aged compared with young adult cardiomyocytes. These data may inform studies using selective enzyme inhibitors/antagonists, available as experimental compounds or clinically approved drugs e.g. remdesivir that has recently been rapidly accepted for compassionate use, to further understand the contribution of these pathways in human cardiomyocytes to disease outcome in COVID-19 patients.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗

bioRxiv2019

Extramacrochaete promotes branch and bouton number via the sequestration of Daughterless in the cytoplasm of neurons.

The class I basic Helix Loop Helix (bHLH) proteins are highly conserved transcription factors that are ubiquitously expressed. A wealth of literature on class I bHLH proteins have shown that these proteins must homodimerize or heterodimerize with tissue specific HLH proteins in order to bind DNA at E box (CANNTG) consensus sequences to control tissue specific transcription. Due to its ubiquitous expression, class I bHLH proteins are also extensively regulated post-translationally, mostly through dimerization. Previously, we reported that in addition to its role in promoting neurogenesis, the class I bHLH protein Daughterless also functions in mature neurons to restrict axon branching and synapse number. Here, we show that part of the molecular logic that specifies how Daughterless functions in neurogenesis is also conserved in neurons. We show that the type V HLH protein Extramacrochaete binds to and represses Daughterless function by sequestering Daughterless to the cytoplasm. This work provides initial insights into the mechanisms underlying the function of Daughterless and Extramacrochatae in neurons while providing a novel understanding of how Extramacrochaetae functions to restricts Daughterless activity within the cell.

neuroscience↗