Transplantation to study satellite cell heterogeneity in skeletal muscle.

Skeletal muscle has a remarkable capacity to regenerate throughout life, which is mediated by its resident muscle stem cells, also called satellite cells. Satellite cells, located periphery to the muscle fibers and underneath the basal lamina, are an indispensable cellular source for muscle regeneration. Satellite cell transplantation into regenerating muscle contributes robustly to muscle repair, thereby indicating that satellite cells indeed function as adult muscle stem cells.

Hepatic posttranscriptional network comprised of CCR4-NOT deadenylase and FGF21 maintains systemic metabolic homeostasis.

Whole-body metabolic homeostasis is tightly controlled by hormone-like factors with systemic or paracrine effects that are derived from nonendocrine organs, including adipose tissue (adipokines) and liver (hepatokines). Fibroblast growth factor 21 (FGF21) is a hormone-like protein, which is emerging as a major regulator of whole-body metabolism and has therapeutic potential for treating metabolic syndrome. However, the mechanisms that control FGF21 levels are not fully understood.

EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions.

Loss of dystrophin expression in Duchenne muscular dystrophy (DMD) causes progressive degeneration of skeletal muscle, which is exacerbated by reduced self-renewing asymmetric divisions of muscle satellite cells. This, in turn, affects the production of myogenic precursors and impairs regeneration and suggests that increasing such divisions may be beneficial. Here, through a small-molecule screen, we identified epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurka) as regulators of asymmetric satellite cell divisions.

Crispr-Cas9 engineered osteogenesis imperfecta type V leads to severe skeletal deformities and perinatal lethality in mice.

Osteogenesis imperfecta (OI) type V is caused by an autosomal dominant mutation in the IFITM5 gene, also known as BRIL. The c.-14C>T mutation in the 5'UTR of BRIL creates a novel translational start site adding 5 residues (MALEP) in frame with the natural coding of BRIL.

FIAT Deletion Increases Bone Mass But Does Not Prevent High-Fat-Diet-Induced Metabolic Complications.

Factor inhibiting activating transcription factor 4 (ATF4)-mediated transcription (FIAT) interacts with ATF4 to repress its transcriptional activity. We performed a phenotypic analysis of Fiat-deficient male mice (Fiat-/Y) at 8 and 16 weeks of age. Microcomputed tomography analysis of the distal femur demonstrated 46% and 13% age-dependent increases in trabecular bone volume and thickness, respectively, in Fiat-/Y mice.

Altered gene dosage confirms the genetic interaction between FIAT and αNAC.

Factor inhibiting ATF4-mediated transcription (FIAT) interacts with Nascent polypeptide associated complex and coregulator alpha (αNAC). In cultured osteoblastic cells, this interaction contributes to maximal FIAT-mediated inhibition of Osteocalcin (Ocn) gene transcription. We set out to demonstrate the physiological relevance of this interaction by altering gene dosage in compound Fiat and Naca (encoding αNAC) heterozygous mice.

SUMOylated αNAC potentiates transcriptional repression by FIAT.

The transcriptional coregulator αNAC (Nascent polypeptide associated complex And Coregulator alpha) and the transcriptional repressor FIAT (Factor Inhibiting ATF4-mediated Transcription) interact but the biological relevance of this interaction remains unclear. The activity of αNAC is extensively modulated by post-translational modifications (PTMs). We identified a novel αNAC PTM through covalent attachment of the Small Ubiquitin-like MOdifier (SUMO1).

Control of Fiat (factor inhibiting ATF4-mediated transcription) expression by Sp family transcription factors in osteoblasts.

FIAT (factor inhibiting ATF4-mediated transcription) represses Osteocalcin gene transcription and inhibits osteoblast activity by heterodimerizing with ATF4 to prevent it from binding DNA. It thus appears important to identify and characterize the molecular mechanisms that control Fiat gene expression in osteoblasts. In silico sequence analysis identified a canonical GC-box within a 1,400 bp region of the proximal Fiat gene promoter.

Combinatorial control of ATF4-dependent gene transcription in osteoblasts.

Osteoblast-specific gene transcription requires interaction between bone cell-specific transcription factors and more widely expressed transcriptional regulators. This is particularly evident for the basic domain-leucine zipper factor activating transcription factor 4 (ATF4), whose activity can be enhanced or inhibited through interaction with other leucine zipper proteins, intermediate filament proteins, components of the basic transcriptional machinery, nuclear matrix attachment molecules, or ubiquitously expressed transcription factors. We discuss the results supporting the relevance of these interactions and present the first evidence of a functional interaction between ATF4, FIAT (factor-inhibiting ATF4-mediated transcription), and αNAC (nascent polypeptide-associated complex and coactivator alpha), three proteins that have been previously shown to associate using various protein-protein interaction assays.