scholarly journals HDAC stimulates gene expression through BRD4 availability in response to IFN and in interferonopathies

2018 ◽  
Vol 215 (12) ◽  
pp. 3194-3212 ◽  
Author(s):  
Isabelle J. Marié ◽  
Hao-Ming Chang ◽  
David E. Levy
Keyword(s):  
Autoimmune Diseases ◽  
Histone Deacetylases ◽  
Elongation Factor ◽  
Positive Function ◽  
Transcriptional Elongation ◽  
Hdac Inhibition ◽  
Transcriptional Initiation ◽  
Inducible Promoters ◽  
The Common

In contrast to the common role of histone deacetylases (HDACs) for gene repression, HDAC activity provides a required positive function for IFN-stimulated gene (ISG) expression. Here, we show that HDAC1/2 as components of the Sin3A complex are required for ISG transcriptional elongation but not for recruitment of RNA polymerase or transcriptional initiation. Transcriptional arrest by HDAC inhibition coincides with failure to recruit the epigenetic reader Brd4 and elongation factor P-TEFb due to sequestration of Brd4 on hyperacetylated chromatin. Brd4 availability is regulated by an equilibrium cycle between opposed acetyltransferase and deacetylase activities that maintains a steady-state pool of free Brd4 available for recruitment to inducible promoters. An ISG expression signature is a hallmark of interferonopathies and other autoimmune diseases. Combined inhibition of HDAC1/2 and Brd4 resolved the aberrant ISG expression detected in cells derived from patients with two inherited interferonopathies, ISG15 and USP18 deficiencies, defining a novel therapeutic approach to ISG-associated autoimmune diseases.

scholarly journals DOT1L Complex Regulates Transcriptional Initiation 1 in Human Cells

2020 ◽  
Author(s):  
Ming Yu ◽  
Robert Roeder ◽  
Aiwei Wu ◽  
Junhong Zhi ◽  
Tian Tian ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Elongation Factor ◽  
Elongation Rate ◽  
Human Cells ◽  
Mixed Lineage Leukemia ◽  
Transcriptional Elongation ◽  
Saga Complex ◽  
Transcriptional Initiation ◽  
Pol Ii ◽  
General Transcription Factors

DOT1L, the only H3K79 methyltransferase in human cells and a homolog of the yeast Dot1, normally forms a complex with AF10, AF17 and ENL/AF9, is dysregulated in most of the cases of mixed lineage leukemia (MLL) and is believed to regulate transcriptional elongation without much evidence. Here we show that DOT1L depletion reduced the global occupancy without affecting the traveling ratio or the elongation rate of Pol II, suggesting it not a major elongation factor. An examination of general transcription factors binding revealed globally reduced TBP and TFIIA occupancies near promoters after DOT1L loss, pointing to a role in transcriptional initiation. Proteomic studies uncovered that DOT1L regulates transcriptional initiation likely by facilitating the recruitment of TFIID. Moreover, ENL, a DOT1L complex subunit with a known role in DOT1L recruitment, also regulates transcriptional initiation. Furthermore, DOT1L stimulates H2B monoubiquitination by limiting the recruitment of human SAGA complex, and the connection between Dot1/DOT1L and SAGA complex is conserved between yeast and human. These results advanced current understanding of roles of DOT1L complex in transcriptional regulation and MLL.

scholarly journals Interaction between P-TEFb and the C-Terminal Domain of RNA Polymerase II Activates Transcriptional Elongation from Sites Upstream or Downstream of Target Genes

2002 ◽  
Vol 22 (1) ◽  
pp. 321-331 ◽  
Author(s):  
Ran Taube ◽  
Xin Lin ◽  
Dan Irwin ◽  
Koh Fujinaga ◽  
B. Matija Peterlin
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Target Genes ◽  
Elongation Factor ◽  
Transcriptional Elongation ◽  
Cyclin T1 ◽  
Positive Transcription Elongation Factor ◽  
Terminal Domain ◽  
Activation Of Transcription

ABSTRACT Transcriptional elongation by RNA polymerase II (RNAPII) is regulated by the positive transcription elongation factor b (P-TEFb). P-TEFb is composed of Cdk9 and C-type cyclin T1 (CycT1), CycT2a, CycT2b, or CycK. The role of the C-terminal region of CycT1 and CycT2 remains unknown. In this report, we demonstrate that these sequences are essential for the activation of transcription by P-TEFb via DNA, i.e., when CycT1 is tethered upstream or downstream of promoters and coding sequences. A histidine-rich stretch, which is conserved between CycT1 and CycT2 in this region, bound the C-terminal domain of RNAPII. This binding was required for the subsequent expression of full-length transcripts from target genes. Thus, P-TEFb could mediate effects of enhancers on the elongation of transcription.

scholarly journals ELL and EAF1 are Cajal Body Components That Are Disrupted in MLL-ELL Leukemia

2003 ◽  
Vol 14 (4) ◽  
pp. 1517-1528 ◽  
Author(s):  
Paul E. Polak ◽  
Federico Simone ◽  
Joseph J. Kaberlein ◽  
Roger T. Luo ◽  
Michael J. Thirman
Keyword(s):  
Rna Polymerase Ii ◽  
Elongation Factor ◽  
Cajal Body ◽  
Leukemia Cells ◽  
Physical Interaction ◽  
Transcriptional Elongation ◽  
Direct Role ◽  
Pol Ii ◽  
Active Transcription

The (11;19)(q23;p13.1) translocation in acute leukemia results in the formation of a chimeric MLL-ELL fusion protein. ELL is an RNA Polymerase II (Pol II) transcriptional elongation factor that interacts with the recently identified EAF1 protein. Here, we show that ELL and EAF1 are components of Cajal bodies (CBs). Although ELL and EAF1 colocalize with p80 coilin, the signature protein of CBs, ELL and EAF1 do not exhibit a direct physical interaction with p80 coilin. Treatment of cells with actinomycin D, DRB, or α-amanitin, specific inhibitors of Pol II, disperses ELL and EAF1 from CBs, indicating that localization of ELL and EAF1 in CBs is dependent on active transcription by Pol II. The concentration of ELL and EAF1 in CBs links the transcriptional elongation activity of ELL to the RNA processing functions previously identified in CBs. Strikingly, CBs are disrupted in MLL-ELL leukemia. EAF1 and p80 coilin are delocalized from CBs in murine MLL-ELL leukemia cells and in HeLa cells transiently transfected with MLL-ELL. Nuclear and cytoplasmic fractionation revealed diminished expression of p80 coilin and EAF1 in the nuclei of MLL-ELL leukemia cells. These studies are the first demonstration of a direct role of CB components in leukemogenesis.

scholarly journals Deubiquitinating enzyme USP21 inhibits HIV-1 replication by downregulating Tat expression

2021 ◽  
Author(s):  
Wenying Gao ◽  
Guangquan Li ◽  
Simin Zhao ◽  
Hong Wang ◽  
Chen Huan ◽  
...  
Keyword(s):  
Viral Infection ◽  
Essential Role ◽  
Elongation Factor ◽  
Accessory Proteins ◽  
Transcriptional Elongation ◽  
Mrna Levels ◽  
Cyclin T1 ◽  
Hiv Drugs ◽  
Hiv 1

Ubiquitination plays an important role in human immunodeficiency virus-1 (HIV-1) infection. HIV proteins such as Vif and Vpx mediate the degradation of the host proteins APOBEC3 and SAMHD1, respectively, through the proteasome pathway. However, whether deubiquitylating enzymes play an essential role in HIV-1 infection is largely unknown. Here, we demonstrate that the deubiquitinase, USP21, potently inhibits HIV-1 production by indirectly downregulating the expression of HIV-1 trans-activator of transcription (Tat), which is essential for transcriptional elongation in HIV-1. USP21 deubiquitylates Tat via its deubiquitinase activity, but a stronger ability to reduce Tat expression compared to Ub-KO showed that other mechanisms may contribute to USP21-mediated inhibition of Tat. Further investigation showed that USP21 downregulates cyclin T1 mRNA levels by increasing methylation of histone K9 in the promoter of cyclin T1, a subunit of the positive transcription elongation factor b (P-TEFb) that interacts with Tat and transactivation response element (TAR) and is required for transcription stimulation and Tat stability. Moreover, USP21 had no effect on the function of other HIV-1 accessory proteins, including Vif, Vpr, Vpx, and Vpu, indicating that USP21 was specific to Tat. These findings improve our understanding of USP21-mediated functional suppression of HIV-1 production. Importance Ubiquitination plays an essential role in viral infection. Deubiquitinating enzymes (DUBs) reverse ubiquitination by cleaving ubiquitins from target proteins, thereby affecting viral infection. The role of the members of the USP family, that comprises the largest subfamily of DUBs, is largely unknown in HIV-1 infection. Here, we screened a series of USP members and found that USP21 inhibits HIV-1 production by specifically targeting Tat, but not the other HIV-1 accessory proteins. Further investigations revealed that USP21 reduces Tat expression in two ways. First, USP21 deubiquitinates polyubiquitinated Tat causing Tat instability, and second USP21 reduces the mRNA levels of cyclin T1 (CycT1), an important component of P-TEFb, that leads 56 to Tat downregulation. Thus, in this study, we report a novel role of the deubiquitinase, USP21, in HIV-1 viral infection. USP21 represents a potentially useful target for the development of novel anti-HIV drugs.

scholarly journals The Role of DNMT and HDACs in the Fetal Programming of Hypertension by Glucocorticoids

2020 ◽  
Vol 2020 ◽  
pp. 1-17 ◽  
Author(s):  
J. Lamothe ◽  
S. Khurana ◽  
S. Tharmalingam ◽  
C. Williamson ◽  
C. J. Byrne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fetal Programming ◽  
Histone Deacetylases ◽  
In Utero ◽  
Dna Methyltransferases ◽  
In Utero Exposure ◽  
Hdac Inhibition ◽  
Adult Rats ◽  
Genetic And Environmental Factors

The causes of hypertension are complex and involve both genetic and environmental factors. Environment changes during fetal development have been linked to adult diseases including hypertension. Studies show that timed in utero exposure to the synthetic glucocorticoid (GC) dexamethasone (Dex) results in the development of hypertension in adult rats. Evidence suggests that in utero stress can alter patterns of gene expression, possibly a result of alterations in the topology of the genome by epigenetic markers such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). The objective of this study was to determine the effects of epigenetic regulators in the fetal programming and the development of adult hypertension. Specifically, this research examined the effects of the HDAC inhibitor valproic acid (VPA) and the DNMT inhibitor 5-aza-2′-deoxycytidine (5aza2DC) on blood pressure (BP) and gene expression in prenatal Dex-programmed rats. Data suggest that both VPA and 5aza2DC attenuated the Dex-mediated development of hypertension and restored BP to control levels. Epigenetic DNMT inhibition (DNMTi) or HDAC inhibition (HDACi) also successfully attenuated elevations in the majority of altered catecholamine (CA) enzyme expression, phenylethanolamine N-methyltransferase (PNMT) protein, and elevated epinephrine (Epi) levels in males. Although females responded to HDACi similar to males, DNMTi drove increased glucocorticoid receptor (GR) and PNMT expression and elevations in circulating Epi in females despite showing normotensive BP.

On everyday academic research

2017 ◽  
pp. 98-134 ◽  
Author(s):  
J. Tirole
Keyword(s):  
Common Good ◽  
Academic Research ◽  
Research Quality ◽  
Economic Research ◽  
Relevant Research ◽  
The Common ◽  
Verification Of Models ◽  
Science And Research

In the fourth chapter of the book “The economy of the common good”, the nature of economics as a science and research practices in their theoretical and empirical aspects are discussed. The author considers the processes of modeling, empirical verification of models and evaluation of research quality. In addition, the features of economic cognition and the role of mathematics in economic research are analyzed, including the example of relevant research in game theory and information theory.

Contemplative Principles of a Non-dual Praxis: the Unmediated Practices of the Tibetan ‘Heart Essence’ (sNying thig) Tradition

2015 ◽  
Vol 31 (2) ◽  
pp. 215-240
Author(s):  
Eran Laish
Keyword(s):  
Contemplative Practice ◽  
Tibetan Buddhist ◽  
Buddhist Tradition ◽  
The Common

This article focuses on the main contemplative principles of the ‘Heart Essence’ (sNying thig), a Tibetan Buddhist tradition that is characterized by a vision of non-duality and primordial wholeness. Due to this vision, which asserts an original reality that is not divided into perceiving subject and perceived object, the ‘Heart Essence’ advocates a contemplative practice that undermines the usual intuitions of temporality and enclosed selfhood. Hence, unlike the common principles of intentional praxis, such as deliberate concentration and gradual purification, the ‘Heart Essence’ affirms four contemplative principles of non-objectiveness, openness, spontaneity and singleness. As these principles transcend intentionality, temporality, and multiplicity, they are seen to directly disclose the nature of primordial awareness, in which the meanings of knowing and being are radically transformed. Therefore, the article will also consider the role of these non-dual contemplative principles in deeply changing our understanding of being and knowing alike.

Hyperstimulation of the immune system as a cause of autoimmune diseases

2020 ◽  
Vol 75 (3) ◽  
pp. 204-213
Author(s):  
Varvara A. Ryabkova ◽  
Leonid P. Churilov ◽  
Yehuda Shoenfeld
Keyword(s):  
Immune System ◽  
Autoimmune Diseases ◽  
Genetic Basis ◽  
Threshold Model ◽  
Subsequent Development ◽  
Threshold Effect ◽  
Successful Management ◽  
Polygenic Inheritance ◽  
Autoimmune Pathology ◽  
The Common

The pathogenesis of autoimmune diseases is very complex and multi-factorial. The concept of Mosaics of Autoimmunity was introduced to the scientific community 30 years ago by Y. Shoenfeld and D.A. Isenberg, and since then new tiles to the puzzle are continuously added. This concept specifies general pathological ideas about the multifactorial threshold model for polygenic inheritance with a threshold effect by the action of a number of external causal factors as applied to the field of autoimmunology. Among the external factors that can excessively stimulate the immune system, contributing to the development of autoimmune reactions, researchers are particularly interested in chemical substances, which are widely used in pharmacology and medicine. In this review we highlight the autoimmune dynamics i.e. a multistep pathogenesis of autoimmune diseases and the subsequent development of lymphoma in some cases. In this context several issues are addressed namely, genetic basis of autoimmunity; environmental immunostimulatory risk factors; gene/environmental interaction; pre-clinical autoimmunity with the presence of autoantibodies; and the mechanisms, underlying lymphomagenesis in autoimmune pathology. We believe that understanding the common model of the pathogenesis of autoimmune diseases is the first step to their successful management.

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