Samara Kiihl

Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK

First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen in cultured human cells. The genetic interaction profiles revealed enzyme–substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications.

Manganese exposure induces microglia activation and dystrophy in the substantia nigra of non-human primates

Chronic manganese (Mn) exposure produces neurological deficits including a form of parkinsonism that is different from Parkinsons disease (PD). In chronic Mn exposure, dopamine neurons in the substantia nigra (SN) do not degenerate but they appear to be dysfunctional. Further, previous studies have suggested that the substantia nigra pars reticulata (SNr) is affected by Mn. In the present study, we investigated whether chronic Mn exposure induces microglia activation in the substantia nigra pars compacta (SNc) and SNr in Cynomolgus macaques. Animals were exposed to different weekly doses of Mn (3.3-5.0, 5.0-6.7, 8.3-10 mg Mn/kg body weight) and microglia were examined in the substantia nigra using LN3 immunohistochemistry. We observed that in control animals, LN3 labeled microglia were characterized by a resting phenotype. However, in Mn-treated animals, microglia increased in number and displayed reactive changes with increasing Mn exposure. This effect was more prominent in the SNr than in the SNc. In the SNr of animals administered the highest Mn dose, microglia activation was the most advanced and included dystrophic changes. Reactive microglia expressed increased iNOS, L-ferritin, and intracellular ferric iron which were particularly prominent in dystrophic compartments. Our observations indicate that moderate Mn exposure produces structural changes on microglia, which may have significant consequences on their function.

Retraction: Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK

This corrects the article DOI: 10.1038/nature10804

Social support of low-income Brazilian mothers related to time to completion of childhood vaccinations

Our study objective was to examine how maternal social support and depressive symptoms are associated with time to completion of childhood vaccinations. We used cross-sectional data from 582 randomly-selected, low-income Brazilian children. Adjusted Cox proportional hazard models were used to estimate time to completing the first three recommended oral polio and diphtheria, pertussis and tetanus (DPT) vaccinations as well as their booster doses. Among only the women with low social support, each ten-point increase on the Medical Outcomes Study—Social Support Scale was associated with a 20% increased chance of completing the first three recommended vaccinations for polio and DPT at any given time (HR = 1.20, 95% CI 1.02–1.42). Although falling short of statistical significance, also among mothers with low social support, we found a suggestive finding of increased social support associated with 25% greater chance of completing polio and DPT booster vaccines at any given time (HR = 1.25, 95% CI 0.98–1.60). There was no association between maternal depressive symptoms and vaccination completion. Among mothers with little social support, increased social support may be important for timely completion of vaccinations in low-income Brazilian children. Longitudinal studies and research on mechanisms explaining associations between maternal social support and childhood vaccination are needed.

Organismal Responses to Hypoxemic Challenges.

As a counterpoint to the volumes of beautiful work exploring how the carotid bodies (CBs) sense and transduce stimuli into neural traffic, this study explored one organismal reflex response to such stimulation. We challenged the anesthetized, paralyzed, artificially ventilated cat with two forms of acute hypoxemia: 10 % O(2)/balance N(2) (hypoxic hypoxia [HH] and carbon monoxide hypoxia [COH]). HH stimulates both CBs and aortic bodies (ABs), whereas COH stimulates only the ABs. Our design was to stimulate both with HH (HHint), then to stimulate only the ABs with COH (COHint); then, after aortic depressor nerve transaction, only the CBs with HH (HHabr), and finally neither with COH (COHabr). We recorded whole animal responses from Group 1 cats (e.g., cardiac output, arterial blood pressure, pulmonary arterial pressure/and vascular resistance) before and after sectioning the aortic depressor nerves. From Group 2 cats (intact) and Group 3 cats (aortic body resected) we recorded the vascular resistance in several organs (e.g., brain, heart, spleen, stomach, pancreas, adrenal glands, eyes). The HHint challenge was the most effective at keeping perfusion pressures adequate to maintain homeostasis in the face of a systemic wide hypoxemia with locally mediated vasodilation. The spleen and pancreas, however, showed a vasoconstrictive response. The adrenals and eyes showed a CB-mediated vasodilation. The ABs appeared to have a significant impact on the pulmonary vasculature as well as the stomach. Chemoreceptors via the sympathetic nervous system play the major role in this organisms response to hypoxemia.

Autonomic regulation of organ vascular resistances during hypoxemia in the cat.

This study aimed to dissect the roles played by the autonomic interoreceptors, the carotid bodies (cbs) and the aortic bodies (abs) on the vascular resistances of several organs in anesthetized, paralyzed, artificially ventilated cats challenged by systemic hypoxemia. Two 15 min challenges stimulated each of 5 animals in two different groups: (1) in the intact group hypoxic hypoxia (10% O2 in N2; HH) stimulated both abs and cbs, increasing neural output to the nucleus tractus solitarius (NTS); (2) in this group carbon monoxide hypoxia (30% O2 in N2 with the addition of CO; COH) stimulated only the abs, increasing neural output to the NTS. (3) In the second group in which their bilateral aortic depressor nerves had been transected only the cbs increased neural output to the NTS during the HH challenge; (4) in this aortic body resected group during COH neither abs nor cbs increased neural traffic to the NTS. CO and 10% O2 reduced Hb saturation to the same level. With the use of radiolabeled microspheres blood flow was measured in a variety of organs. Organ vascular resistance was calculated by dividing the aortic pressure by that organs blood flow. The spleen and pancreas revealed a vasoconstriction in the face of systemic hypoxemia, thought to be sympathetic nervous system (SNS)-mediated. The adrenals and the eyes vasodilated only when cbs were stimulated. Vasodilation in the heart and diaphragm showed no effect of chemoreceptor stimulated increase in SNS output. Different chemoreceptor involvement had different effects on the organs.

Erratum: Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK (Nature (2012) 482 (251-255) DOI:10.1038/nature10804)

This corrects the article DOI: 10.1038/nature10804

Retraction Note to: Retraction: Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK

This corrects the article DOI: 10.1038/nature10804

Hydrogen sulfide acting at the carotid body and elsewhere in the organism

H2S, the most recently explored gasotransmitter, has been found to have actions in at least three types of tissues.