scholarly journals Recapitulation of erythropoiesis in congenital dyserythropoietic anaemia type I (CDA-I) identifies defects in differentiation and nucleolar abnormalities

Haematologica ◽  
2020 ◽  
pp. 0-0
Author(s):  
Caroline Scott ◽  
Damien J. Downes ◽  
Jill M. Brown ◽  
Robert Beagrie ◽  
Aude-Anais Olijnik ◽  
...  
Keyword(s):  
Culture System ◽  
Erythroid Differentiation ◽  
Chromatin Accessibility ◽  
Type I ◽  
Genetic Abnormality ◽  
Inherited Disorders ◽  
Rare Form ◽  
First Time ◽  
Terminal Erythroid Differentiation

The investigation of inherited disorders of erythropoiesis has elucidated many of the principles underlying the production of normal red blood cells and how this is perturbed in human disease. Congenital Dyserythropoietic Anaemia type 1 (CDA-I) is a rare form of anaemia caused by mutations in two genes of unknown function: CDAN1 and CDIN1 (previously called C15orf41), whilst in some cases, the underlying genetic abnormality is completely unknown. Consequently, the pathways affected in CDA-I remain to be discovered. To enable detailed analysis of this rare disorder we have validated a culture system which recapitulates all of the cardinal haematological features of CDA-I, including the formation of the pathognomonic ‘spongy’ heterochromatin seen by electron microscopy. Using a variety of cell and molecular biological approaches we discovered that erythroid cells in this condition show a delay during terminal erythroid differentiation, associated with increased proliferation and widespread changes in chromatin accessibility. We also show that the proteins encoded by CDAN1 and CDIN1 are enriched in nucleoli which are structurally and functionally abnormal in CDA-I. Together these findings provide important pointers to the pathways affected in CDA-I which for the first time can now be pursued in the tractable culture system utilised here.

Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency

Blood ◽  
2021 ◽  
Author(s):  
Yaomei Wang ◽  
Wei Li ◽  
Vince Schulz ◽  
Huizhi Zhao ◽  
Xiaoli Qu ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Chromatin Condensation ◽  
Erythroid Differentiation ◽  
Chromatin Accessibility ◽  
Erythroid Cell ◽  
Global Changes ◽  
Human Cd34 ◽  
Wide Range ◽  
Terminal Erythroid Differentiation

Histone deacetylases (HDACs) are a group of enzymes catalyzing the removal of acetyl groups from histone and non-histone proteins. HDACs have been shown to play diverse functions in a wide range of biological processes. However, their roles in mammalian erythropoiesis remain to be fully defined. We show here that of the eleven classic HDAC family members, six of them (HDAC 1,2,3 and HDAC 5,6,7) are expressed in human erythroid cells with HDAC5 most significantly up regulated during terminal erythroid differentiation. Knockdown of HDAC5 by either shRNA or siRNA in human CD34+ cells followed by erythroid cell culture led to increased apoptosis, decreased chromatin condensation, and impaired enucleation of erythroblasts. Biochemical analyses revealed that HDAC5 deficiency resulted in activation of p53 in association with increased acetylation of p53. Furthermore, while acetylation of histone 4 (H4) is decreased during normal terminal erythroid differentiation, HDAC5 deficiency led to increased acetylation of H4 (K12) in late stage erythroblasts. This increased acetylation was accompanied by decreased chromatin condensation, implying a role for H4 (K12) deacetylation in chromatin condensation. ATAC-seq and RNA-seq analyses revealed that HDAC5 knockdown leads to increased chromatin accessibility genome wide and global changes in gene expression. Moreover, pharmacological inhibition of HDAC5 by the inhibitor LMK235 also led to increased H4 acetylation, impaired chromatin condensation and enucleation. Taken together, our findings have uncovered previously unrecognized roles and molecular mechanisms of action for HDAC5 in human erythropoiesis. These results may provide insights into understanding the anemia associated with HDAC inhibitor treatment.

scholarly journals Regulatory association of long noncoding RNAs and chromatin accessibility facilitates erythroid differentiation

2021 ◽  
Author(s):  
Yunxiao Ren ◽  
Junwei Zhu ◽  
Yuanyuan Han ◽  
Pin Li ◽  
Jing Wu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Erythroid Differentiation ◽  
Chromatin Accessibility ◽  
Human Cord Blood ◽  
Erythroid Progenitor ◽  
Integrated Network ◽  
Hematopoietic Stem ◽  
Multipotent Progenitor Cells ◽  
Tf Gene ◽  
Terminal Erythroid Differentiation

Erythroid differentiation is a dynamic process regulated by multiple factors, while the interaction between long non-coding RNAs and chromatin accessibility and its influence on erythroid differentiation remains unclear. To elucidate this interaction, we employed hematopoietic stem cells, multipotent progenitor cells, common myeloid progenitor cells, megakaryocyte-erythroid progenitor cells, and erythroblasts from human cord blood as an erythroid differentiation model to explore the coordinated regulatory functions of lncRNAs and chromatin accessibility by integrating RNA-Seq and ATAC-Seq data. We revealed that the integrated network of chromatin accessibility and lncRNAs exhibits stage-specific changes throughout the erythroid differentiation process, and that the changes at the EB stage of maturation are dramatic. We identified a subset of stage-specific lncRNAs and transcription factors (TFs) that associate with chromatin accessibility during erythroid differentiation, in which lncRNAs are key regulators of terminal erythroid differentiation via a lncRNA-TF-gene network. LncRNA PCED1B-AS1 was revealed to regulate terminal erythroid differentiation by coordinating GATA1 dynamically binding to the chromatin and interacting with cytoskeleton network during erythroid differentiation. DANCR, another lncRNA that is highly expressed at the MEP stage, was verified to promote erythroid differentiation by compromising megakaryocyte differentiation and coordinating with chromatin accessibility and TFs, such as RUNX1. Overall, our results identified the associated network of lncRNAs and chromatin accessibility in erythropoiesis and provide novel insights into erythroid differentiation and abundant resources for further study.

scholarly journals Runx1 promotes murine erythroid progenitor proliferation and inhibits differentiation by preventing Pu.1 downregulation

2019 ◽  
Vol 116 (36) ◽  
pp. 17841-17847 ◽  
Author(s):  
Michael A. Willcockson ◽  
Samuel J. Taylor ◽  
Srikanta Ghosh ◽  
Sean E. Healton ◽  
Justin C. Wheat ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Terminal Differentiation ◽  
Erythroid Differentiation ◽  
Chromatin Accessibility ◽  
Erythroid Cells ◽  
Erythroid Progenitors ◽  
Down Regulation ◽  
Erythroid Progenitor ◽  
Terminal Erythroid Differentiation ◽  
In Erythroid Cells

Pu.1 is an ETS family transcription factor (TF) that plays critical roles in erythroid progenitors by promoting proliferation and blocking terminal differentiation. However, the mechanisms controlling expression and down-regulation of Pu.1 during early erythropoiesis have not been defined. In this study, we identify the actions of Runx1 and Pu.1 itself at the Pu.1 gene Upstream Regulatory Element (URE) as major regulators of Pu.1 expression in Burst-Forming Unit erythrocytes (BFUe). During early erythropoiesis, Runx1 and Pu.1 levels decline, and chromatin accessibility at the URE is lost. Ectopic expression of Runx1 or Pu.1, both of which bind the URE, prevents Pu.1 down-regulation and blocks terminal erythroid differentiation, resulting in extensive ex vivo proliferation and immortalization of erythroid progenitors. Ectopic expression of Runx1 in BFUe lacking a URE fails to block terminal erythroid differentiation. Thus, Runx1, acting at the URE, and Pu.1 itself directly regulate Pu.1 levels in erythroid cells, and loss of both factors is critical for Pu.1 down-regulation during terminal differentiation. The molecular mechanism of URE inactivation in erythroid cells through loss of TF binding represents a distinct pattern of Pu.1 regulation from those described in other hematopoietic cell types such as T cells which down-regulate Pu.1 through active repression. The importance of down-regulation of Runx1 and Pu.1 in erythropoiesis is further supported by genome-wide analyses showing that their DNA-binding motifs are highly overrepresented in regions that lose chromatin accessibility during early erythroid development.

scholarly journals The dynamic interactive network of long non-coding RNAs and chromatin accessibility facilitates erythroid differentiation

2021 ◽  
Author(s):  
Yunxiao Ren ◽  
Junwei Zhu ◽  
Yuanyuan Han ◽  
Pin Li ◽  
Hongzhu Qu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Specific Interaction ◽  
Erythroid Differentiation ◽  
Chromatin Accessibility ◽  
List Type ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Interactive Network ◽  
Non Coding Rnas ◽  
Terminal Erythroid Differentiation

AbstractErythroid differentiation is a dynamic process regulated by multiple factors, while the interaction between long non-coding RNAs and chromatin accessibility and its influence on erythroid differentiation remains unclear. To elucidate this interaction, we employed hematopoietic stem cells, multipotent progenitor cells, common myeloid progenitor cells, megakaryocyte-erythroid progenitor cells, and erythroblasts from human cord blood as an erythroid differentiation model to explore the coordinated regulatory functions of lncRNAs and chromatin accessibility in erythropoiesis by integrating RNA-Seq and ATAC-Seq data. We revealed that the integrated network of chromatin accessibility and LncRNAs exhibits stage-specific changes throughout the erythroid differentiation process, and that the changes at the EB stage of maturation are dramatic. We identified a subset of stage-specific lncRNAs and transcription factors (TFs) that coordinate with chromatin accessibility during erythroid differentiation, in which lncRNAs are key regulators of terminal erythroid differentiation via a lncRNA-TF-gene network. LncRNA PCED1B-AS1 was revealed to regulate terminal erythroid differentiation by coordinating GATA1 dynamically binding to the chromatin during erythroid differentiation. DANCR, another lncRNA that is highly expressed at the MEP stage, was verified to promote erythroid differentiation by compromising megakaryocyte differentiation and coordinating with chromatin accessibility and TFs, such as RUNX1. Overall, our results identified the interactive network of lncRNAs and chromatin accessibility in erythropoiesis and provide novel insights into erythroid differentiation and abundant resources for further study.Key PointsLncRNAs regulate erythroid differentiation through coordinating with chromatin accessibility.The integrative multi-omics analysis reveals stage-specific interaction network of LncRNAs and chromatin accessibility in erythropoiesis.

scholarly journals The role of Ikaros in human erythroid differentiation

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1138-1146 ◽  
Author(s):  
Marilyne Dijon ◽  
Florence Bardin ◽  
Anne Murati ◽  
Michèle Batoz ◽  
Christian Chabannon ◽  
...  
Keyword(s):  
Culture System ◽  
Myeloid Cells ◽  
Erythroid Differentiation ◽  
Relative Increase ◽  
Dominant Negative ◽  
Erythroid Cells ◽  
Cd34 Cells ◽  
First Time ◽  
Erythroid Development

Abstract Ikaros—a factor that positively or negatively controls gene transcription—is active in murine adult erythroid cells, and involved in fetal to adult globin switching. Mice with Ikaros mutations have defects in erythropoiesis and anemia. In this paper, we have studied the role of Ikaros in human erythroid development for the first time. Using a gene-transfer strategy, we expressed Ikaros 6 (Ik6)—a known dominant-negative protein that interferes with normal Ikaros activity—in cord blood or apheresis CD34+ cells that were induced to differentiate along the erythroid pathway. Lentivirally induced Ik6-forced expression resulted in increased cell death, decreased cell proliferation, and decreased expression of erythroid-specific genes, including GATA1 and fetal and adult globins. In contrast, we observed the maintenance of a residual myeloid population that can be detected in this culture system, with a relative increase of myeloid gene expression, including PU1. In secondary cultures, expression of Ik6 favored reversion of sorted and phenotypically defined erythroid cells into myeloid cells, and prevented reversion of myeloid cells into erythroid cells. We conclude that Ikaros is involved in human adult or fetal erythroid differentiation as well as in the commitment between erythroid and myeloid cells.

Comparative Study of effectiveness of mobilization with movement (MWM) and End range mobilization (ERM) techniques in frozen shoulder

2018 ◽  
Vol 4 (4) ◽  
pp. 519-522
Author(s):  
Jeyakumar S ◽  
Jagatheesan Alagesan ◽  
T.S. Muthukumar
Keyword(s):  
Range Of Motion ◽  
Frozen Shoulder ◽  
Type I ◽  
Mean Values ◽  
Functional Activities ◽  
Group A ◽  
The Mean ◽  
Group B

Background: Frozen shoulder is disorder of the connective tissue that limits the normal Range of motion of the shoulder in diabetes, frozen shoulder is thought to be caused by changes to the collagen in the shoulder joint as a result of long term Hypoglycemia. Mobilization is a therapeutic movement of the joint. The goal is to restore normal joint motion and rhythm. The use of mobilization with movement for peripheral joints was developed by mulligan. This technique combines a sustained application of manual technique “gliding” force to the joint with concurrent physiologic motion of joint, either actively or passively. This study aims to find out the effects of mobilization with movement and end range mobilization in frozen shoulder in Type I diabetics. Materials and Methods: 30 subjects both male and female, suffering with shoulder pain and clinically diagnosed with frozen shoulder was recruited for the study and divided into two groups with 15 patients each based on convenient sampling method. Group A patients received mobilization with movement and Group B patients received end range mobilization for three weeks. The outcome measurements were SPADI, Functional hand to back scale, abduction range of motion using goniometer and VAS. Results: The mean values of all parameters showed significant differences in group A as compared to group B in terms of decreased pain, increased abduction range and other outcome measures. Conclusion: Based on the results it has been concluded that treating the type 1 diabetic patient with frozen shoulder, mobilization with movement exercise shows better results than end range mobilization in reducing pain and increase functional activities and mobility in frozen shoulder.

Antidiabetic effect of Psychotria malayana Jack in induced type 1 diabetic rat

MEDISAINS ◽  
2020 ◽  
Vol 18 (1) ◽  
pp. 19
Author(s):  
Fairuz Fairuz ◽  
Hasna Dewi ◽  
Humaryanto Humaryanto
Keyword(s):  
Blood Glucose ◽  
Side Effects ◽  
Type I Diabetes ◽  
Langerhans Cell ◽  
Diabetic Rat ◽  
Type I ◽  
Antidiabetic Effect ◽  
Glucose Levels ◽  
Blood Glucose Levels

Background: Therapies for hyperglycemic treatment, including insulin and oral diabetes medications, have been confirmed to cause several side effects. Thus, finding new drugs with fewer side effects is of high importance. Salung leaf herb (Psychotria malayana Jack) reported used in traditional societies as a treatment for diabetes. However, the scientific proof of this plant for diabetes treatment is still lacking.Objective: To evaluate the antidiabetic effect of the P. malayana jack in induced type 1 diabetic rats by assessing blood glucose level and pancreatic cells in white rats.Methods: Alloxan used to induce type I diabetes. Rats randomly divided into six groups. A Group P1 received 250 mg/kg BW; group P2 received 500 mg/kg BW, group P3 received 1000 mg/kg BW. While group 4 basal received no treatment, group 5 received distilled water as a negative control, and group 6 received glibenclamide as a positive control. Medications are given for six days. Glucose levels were measured, and observation of pancreatic Langerhans cell damages.Results:  A decrease in blood glucose levels observed in all treatment groups. The most significant reduction (49.76%; 1000 mg/kg BW) occurred in the P3 group. Morphological features of pancreatic Langerhans cell damage were slightly high in the P1 group.Conclusion: P. malayana Jack can consider having an antidiabetic effect in a type 1 diabetic rat by reducing blood glucose levels.

scholarly journals Central precocious puberty in a girl with LEGIUS syndrome: an accidental association?

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Valentina Orlandi ◽  
Paolo Cavarzere ◽  
Laura Palma ◽  
Rossella Gaudino ◽  
Franco Antoniazzi
Keyword(s):  
Genetic Analysis ◽  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Neurofibromatosis Type ◽  
Case Presentation ◽  
New Variant ◽  
Legius Syndrome ◽  
Timing Of Puberty ◽  
First Time

Abstract Background Central precocious puberty is a condition characterized by precocious activation of the hypothalamic-pituitary-gonadal axis. It may be idiopathic or secondary to organic causes, including syndromes such as Neurofibromatosis type 1 (NF1). Case presentation We presented a girl of 6 years and 10 months with almost 11 café-au-lait skin macules, without other clinical or radiological signs typical of NF1, and with a central precocious puberty. Genetic analysis evidenced the new variant NM-152594.2:c.304delAp. (Thr102Argfs*19) in SPRED1 gene, which allowed to diagnose Legius syndrome. Conclusions We report for the first time a case of central precocious puberty in a girl with Legius syndrome. The presence of central precocious puberty in a child with characteristic café-au-lait macules should suggest pediatricians to perform genetic analysis in order to reach a definitive diagnosis. Further studies on timing of puberty in patients with RASopathies are needed to better elucidate if this clinical association is casual or secondary to their clinical condition.

scholarly journals Orexin A Enhances Pro-Opiomelanocortin Transcription Regulated by BMP-4 in Mouse Corticotrope AtT20 Cells

2021 ◽  
Vol 22 (9) ◽  
pp. 4553
Author(s):  
Satoshi Fujisawa ◽  
Motoshi Komatsubara ◽  
Naoko Tsukamoto-Yamauchi ◽  
Nahoko Iwata ◽  
Takahiro Nada ◽  
...  
Keyword(s):  
Stress Responses ◽  
Endocrine Function ◽  
Type I ◽  
Orexin A ◽  
Protein Levels ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Crh Receptor Type 1

Orexin is expressed mainly in the hypothalamus and is known to activate the hypothalamic–pituitary–adrenal (HPA) axis that is involved in various stress responses and its resilience. However, the effects of orexin on the endocrine function of pituitary corticotrope cells remain unclear. In this study, we investigated the roles of orexin A in pro-opiomelanocortin (POMC) transcription using mouse corticotrope AtT20 cells, focusing on the bone morphogenetic protein (BMP) system expressed in the pituitary. Regarding the receptors for orexin, type 2 (OXR2) rather than type 1 (OX1R) receptor mRNA was predominantly expressed in AtT20 cells. It was found that orexin A treatment enhanced POMC expression, induced by corticotropin-releasing hormone (CRH) stimulation through upregulation of CRH receptor type-1 (CRHR1). Orexin A had no direct effect on the POMC transcription suppressed by BMP-4 treatment, whereas it suppressed Smad1/5/9 phosphorylation and Id-1 mRNA expression induced by BMP-4. It was further revealed that orexin A had no significant effect on the expression levels of type I and II BMP receptors but upregulated inhibitory Smad6/7 mRNA and protein levels in AtT20 cells. The results demonstrated that orexin A upregulated CRHR signaling and downregulated BMP-Smad signaling, leading to an enhancement of POMC transcription by corticotrope cells.

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