Pathologie et médecine de laboratoire // Pathology and Laboratory Medicine

Permanent URI for this collectionhttps://hdl.handle.net/10393/12927

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Retinoid X Receptor Signalling in the Specification of Skeletal Muscle Lineage
(2012-08-24) Le May, Melanie; Li, Qiao
Regulation of Myf5 Early Enhancer by Histone Acetyltransferase p300 during Stem Cell Differentiation
(2012-05-18) Francetic, Tanja; Le May, Melanie; Hamed, Munerah; Mach, Hymn; Meyers, David; Cole, Philip A.; Chen, Jihong; Li, Qiao
Skeletal myogenesis is an intricate process coordinated temporally by multiple myogenic regulatory factors (MRF) including Myf5, which is the first MRF expressed and marks the commitment of skeletal muscle lineage. The expression of Myf5 gene during early embryogenesis is controlled by a set of enhancer elements, and requires the histone acetyltransferase (HAT) activity of transcriptional coactivator p300. However, it is unclear as to how different regulatory signals converge at enhancer elements to regulate early Myf5 gene expression, and if p300 is directly involved. We show here that p300 associates with the Myf5 early enhancer at the early stage of stem cell differentiation, and its HAT activity is important for the recruitment of β-catenin to this early enhancer. In addition, histone H3-K27 acetylation, but not H3-K9/14, is intimately connected to the p300 HAT activity. Thus, p300 is directly involved in the regulation of the Myf5 early enhancer, and is important for specific histone acetylation and transcription factor recruitment. This connection of p300 HAT activity with H3-K27 acetylation and β-catenin signalling during myogenic differentiation in vitro offers a molecular insight into the enhancer-elements participation observed in embryonic development. In addition, pluripotent stem cell differentiation is a valuable system to dissect the signal-dependent regulation of specific enhancer element during cell fate determinations.
Life and death of transcriptional co-activator p300
(2011) Qiao, Li; Chen, Jihong
Transcriptional co-activator p300, which contains an intrinsic histone acetyltransferase activity, is required for an array of important cellular processes. Tight control of p300 function is critical to ensure precise histone acetylation and gene activation. Dysregulation of p300 has been implicated in many types of diseases and numerous studies have examined the functional requirement of p300 to act as a co-activator or as an acetyltransferase for other transcription regulators. Few, however, have tackled how p300 itself is regulated and if posttranslational modification and spatial distribution are means of p300 regulation. In this article, we present a current view on the molecular mechanisms by which the activity and stability of p300 is regulated.
Contribution of Retinoid X Receptor Signaling to the Specification of Skeletal Muscle Lineage
(2011) Qiao, Li; LeMay, Melanie; Mach, Hymn; Lacroix, Natascha; Hou, Chenchen; Chen, Jihong
Pluripotent stem cells possess a tremendous potential for the treatment of many diseases because of their capacity to differentiate into a variety of cell lineages. However, they provide little promise for muscle-related diseases, mainly because of the lack of small molecule inducers to efficiently direct myogenic conversion. Retinoic acid, acting through the retinoic acid receptor (RAR) and retinoid X receptor (RXR), affects stem cell fate determination in a concentration-dependent manner, but it only has a modest efficacy on the commitment of ES cells into skeletal muscle lineage. The RXR is very important for embryonic development but is generally considered to act as a silent partner of RAR in a non-permissive mode. In this study, we have examined whether activation of the RXR by rexinoid or RXRspecific signaling play a role in the specification of stem cells into muscle lineage. Our findings demonstrate that mouse ES cells generate skeletal myocytes effectively upon treatment with rexinoid at the early stage of differentiation and that on a molecular level, rexinoid-enhanced myogenesis simulates the sequential events observed in vivo. Moreover, RXR-mediated myogenic conversion requires the function of -catenin but not RAR. Our studies establish the feasibility of applying the RXR agonist in cell-based therapies to treat muscle-related diseases. The aptitude of mouse ES cells to generate skeletal myocytes following rexinoid induction also provides a model system to study the convergence of different signaling pathways in myogenesis.
Promoter context determines the role of proteasome in ligand-dependent occupancy of retinoic acid responsive elements
(2011-01-18) Li, Qiao; Chen, Jihong; Abed, Mahmoud; Higazi, Aliaa
Retinoid acid receptors are DNA-binding proteins mediating the biological effects of ligands through transcriptional activation. It is known that the activity of the 26S proteasome is important for nuclear receptor-activated gene transcription. However, the molecular mechanism by which the 26S proteasome participates in this process is not well understood. Here we report that the proteasome activity is essential for ligand-dependent interaction of RAR with its co-regulators such as SRC, p300 and RXR. We also determined that the proteasome activity is required for the association of liganded RAR to the genomic DNA and, consequently, for the recruitment of the coactivator complex to the retinoic acid responsive elements. Moreover, the requirement of proteasome activity for the activator activity of RAR is determined by the promoter context. Our study suggests that the 26S proteasome regulates directly the activity of RAR as an activator.

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