Summary A common feature of sex chromosomes is coordinated regulation of X-linked genes in one sex. Drosophila melanogaster males have one X chromosome, while females have two. The resulting imbalance in gene dosage is corrected by increased expression from the single X chromosome of males, a process known as dosage compensation. In flies, compensation involves recruitment of the Male Specific Lethal (MSL) complex to X-linked genes and modification of chromatin to increase expression. The extraordinary selectivity of the MSL complex for the X chromosome has never been explained. We previously demonstrated that the siRNA pathway, and siRNA from a family of X-linked satellite repeats (1.688X repeats), promote X-recognition. Now we test the ability of 1.688X DNA to attract compensation to genes nearby, and report that autosomal integration of 1.688X repeats increases MSL recruitment and gene expression in surrounding regions. Placement of 1.688X repeats opposite a lethal autosomal deletion achieves partial rescue of males, demonstrating functional compensation of autosomal chromatin. Females block formation of the MSL complex and are not rescued. The 1.688X repeats are therefore cis-acting elements that guide dosage compensation. Furthermore, 1.688X siRNA enhances rescue of males with a lethal deletion, but only when repeat DNA is present on the intact homolog. We propose that the siRNA pathway promotes X recognition by enhancing the ability of 1.688X DNA to attract compensation in cis. The dense and near-exclusive distribution of 1.688X sequences along the X chromosome suggests that they play a primary role in determining X identity during dosage compensation.

Noncoding RNAs (ncRNAs) are remarkably powerful, flexible, and pervasive cellular regulators. The involvement of these molecules in virtually all aspects of eukaryotic chromatin function is notable. Long and short ncRNAs play broadly complementary roles in these processes. Short ncRNAs underlie a programmable system of chromatin modification that silences mobile elements, identifies boundaries, and initiates the formation of constitutive heterochromatin in yeast. In contrast, long noncoding RNAs (lncRNAs) enforce developmentally appropriate expression and switch gene expression programs. lncRNAs accomplish this through diverse mechanisms, but often by modulating the activity or localization of chromatin regulatory complexes. Both long and short ncRNAs play key roles in organization of complex genomes of higher eukaryotes, and their coordinated actions appear to underlie some of the more dramatic examples of epigenetic regulation. This review contrasts well-studied examples of chromatin regulation by RNA and introduces examples of coordination between these systems.

Aims Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor for endogenous medium/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress. Methods and Results In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodeling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-days post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signaling and oxylipin synthesis as well as reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signaling-deficient Ffar4 R270H polymorphism correlated with eccentric remodeling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC. Conclusions Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.

Sickle cell disease (SCD) is a genetic blood disorder that impacts millions of individuals worldwide. SCD is characterized by debilitating pain that can begin during infancy and may continue to increase throughout life. This pain can be both acute and chronic. A characteristic feature specific to acute pain in SCD occurs during vaso‐occlusive crisis (VOC) due to the blockade of capillaries with sickle red blood cells. The acute pain of VOC is intense, unpredictable, and requires hospitalization. Chronic pain occurs in a significant population with SCD. Treatment options for sickle pain are limited and primarily involve the use of opioids. However, long‐term opioid use is associated with numerous side effects. Thus, pain management in SCD remains a major challenge. Humanized transgenic mice expressing exclusively human sickle hemoglobin show features of pain and pathobiology similar to that in patients with SCD. Therefore, these mice offer the potential for investigating the mechanisms of pain in SCD and allow for development of novel targeted analgesic therapies. © 2018 by John Wiley & Sons, Inc.

247) Background: Non-resolving activation of immune responses is central to the pathogenesis ofheart failure (HF). Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor (GPR) for medium- and long-chain fatty acids (FA) that regulates metabolism and attenuates inflammation in diabetes and obesity. Here, we tested the hypothesis that Ffar4 functions as a cardioprotective nutrient sensor that resolves inflammation to maintain cardiac homeostasis. Methods: Mice with systemic deletion of Ffar4 (Ffar4KO) were subjected to pressure overloadby transverse aortic constriction (TAC). Transcriptome analysis of cardiac myocytes was performed three days post-TAC. Additionally, Ffar4-mediated effects on inflammatory oxylipin production in cardiac myocytes and oxylipin composition in plasma lipoproteins were evaluated. Results: In Ffar4KO mice, TAC induced more severe remodeling, identifying an entirely novelcardioprotective role for Ffar4 in the heart. Transcriptome analysis 3-days post-TAC indicated a failure to induce cell death and inflammatory genes in Ffar4KO cardiac myocytes, as well as a specific failure to induce cytoplasmic phospholipase A2a (cPLA2a) signaling genes. In cardiac myocytes, Ffar4 signaling through cPLA2a-cytochrome p450 w/w-1 hydroxylase induced production of the EPA-derived anti-inflammatory oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Systemically, loss of Ffar4 altered oxylipin content in circulating plasma lipoproteins consistent with a loss of anti-inflammatory oxylipins at baseline, and inability to produce both pro-inflammatory and pro-resolving oxylipins following TAC. Finally, we confirmed that Ffar4 is expressed in human heart and down-regulated in HF. Conclusions: Our results identify a novel function for Ffar4 in the heart as a FA nutrient sensorthat resolves inflammation to maintain cardiac homeostasis.Keywords: Free fatty acid receptor 4 (Ffar4), GPR120, heart failure, cytoplasmic phospholipase A2a (cPLA2a), 18-hydroxyeicosapentaenoic acid (18-HEPE)