Page last updated: 2024-10-24

regulation of megakaryocyte differentiation

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of megakaryocyte differentiation. [GOC:go_curators]

Megakaryocyte differentiation, the process by which hematopoietic stem cells commit to and mature into megakaryocytes, the large polyploid cells responsible for producing platelets, is a complex and tightly regulated process. It involves a cascade of signaling events, transcription factor activation, and epigenetic modifications, ensuring appropriate platelet production and maintaining hemostasis.

**1. Commitment and Progenitor Expansion:**

* Hematopoietic stem cells (HSCs) receive signals from the bone marrow microenvironment, including cytokines such as thrombopoietin (TPO), interleukin-3 (IL-3), and interleukin-11 (IL-11), triggering the commitment of HSCs towards the megakaryocyte lineage.
* These cytokines activate downstream signaling pathways, such as the JAK-STAT pathway, leading to the expression of transcription factors crucial for megakaryocyte development, including GATA-1, FOG1, and FLI1.
* Progenitor cells, like megakaryocyte progenitors (MkPs), proliferate and expand in response to these signals, preparing for the subsequent differentiation steps.

**2. Maturation and Polyploidization:**

* As megakaryocyte progenitors differentiate, they undergo endomitosis, a unique form of cell division where nuclear DNA replicates without cytokinesis. This results in the formation of large, polyploid megakaryocytes with multiple copies of the genome.
* This polyploidization is essential for platelet production, as each megakaryocyte can produce thousands of platelets.
* The transcription factors GATA-1, FOG1, and FLI1 continue to play a crucial role in regulating this process, along with other factors such as NF-E2 and RUNX1.

**3. Megakaryocyte Maturation and Platelet Formation:**

* As megakaryocytes mature, they undergo morphological changes, including the development of proplatelets, long cytoplasmic extensions filled with platelet precursors.
* These proplatelets extend into the bloodstream and eventually fragment into individual platelets.
* Platelets are essential for hemostasis, the process of stopping bleeding, by forming a platelet plug at the site of vascular injury.
* This process is further influenced by a complex interplay of signaling pathways, including the integrin-mediated adhesion, coagulation factors, and the release of platelet-derived growth factors.

**4. Regulation of Megakaryocyte Differentiation:**

* The regulation of megakaryocyte differentiation is a tightly controlled process, ensuring appropriate platelet production and preventing excessive bleeding or thrombosis.
* This regulation is influenced by various factors, including:
* **Cytokines:** TPO is the primary regulator of megakaryocyte differentiation, stimulating proliferation and maturation. Other cytokines like IL-3, IL-11, and stem cell factor (SCF) also contribute.
* **Transcription Factors:** GATA-1, FOG1, FLI1, NF-E2, RUNX1, and others orchestrate the expression of genes essential for megakaryocyte development and platelet formation.
* **Epigenetic Modifications:** DNA methylation, histone modifications, and non-coding RNAs influence the accessibility and expression of genes involved in megakaryopoiesis.
* **Microenvironment:** The bone marrow microenvironment provides essential support for megakaryocyte development, including cell-cell interactions, signaling molecules, and physical cues.

**5. Dysregulation and Disease:**

* Disruptions in megakaryocyte differentiation can lead to various hematological disorders:
* **Thrombocytopenia:** Low platelet counts due to impaired megakaryocyte differentiation or production.
* **Thrombocytosis:** Elevated platelet counts due to increased megakaryocyte activity.
* **Myeloproliferative neoplasms:** Cancers affecting the bone marrow, often involving megakaryocyte dysfunction.
* **Congenital amegakaryocytic thrombocytopenia (CAMT):** Rare genetic disorder characterized by the absence of megakaryocytes and platelets.

**Conclusion:** Megakaryocyte differentiation is a multi-step process requiring intricate coordination of signaling pathways, transcription factors, and epigenetic modifications. The process is tightly regulated to ensure adequate platelet production and maintain hemostasis. Dysregulation of megakaryopoiesis can lead to various hematological disorders, highlighting the importance of understanding this complex biological process for diagnosis and therapeutic interventions.'"

Proteins (6)

ProteinDefinitionTaxonomy
Protein arginine N-methyltransferase 1A protein arginine N-methyltransferase 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q99873]Homo sapiens (human)
Protein arginine N-methyltransferase 6A protein arginine N-methyltransferase 6 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96LA8]Homo sapiens (human)
Lethal(3)malignant brain tumor-like protein 1A lethal(3)malignant brain tumor-like protein 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9Y468]Homo sapiens (human)
Protein arginine N-methyltransferase 1A protein arginine N-methyltransferase 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q99873]Homo sapiens (human)
Protein arginine N-methyltransferase 6A protein arginine N-methyltransferase 6 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96LA8]Homo sapiens (human)
Protein-lysine 6-oxidaseA protein-lysine 6-oxidase that is encoded in the genome of human. [PRO:DNx, UniProtKB:P28300]Homo sapiens (human)

Compounds (37)

CompoundDefinitionClassesRoles
pyrithionepyrithione : A pyridinethione that is pyridine-2(1H)-thione in which the hydrogen attached to the nitrogen is replaced by a hydroxy group. It is a Zn(2+) ionophore; the zinc salt is used as an antifungal and antibacterial agent.

pyrithione: split from cephalosporin molecule; some metal complexes of this have fumarate reductase inhibitory activity and may be useful against trypanosomes; RN given refers to parent cpd; structure
monohydroxypyridine;
pyridinethione
ionophore
aminopropionitrileAminopropionitrile: Reagent used as an intermediate in the manufacture of beta-alanine and pantothenic acid.aminopropionitrileantineoplastic agent;
antirheumatic drug;
collagen cross-linking inhibitor;
plant metabolite
bifemelanebifemelane: structure given in first sourcediarylmethane
chlorpheniraminechlorphenamine : A tertiary amino compound that is propylamine which is substituted at position 3 by a pyridin-2-yl group and a p-chlorophenyl group and in which the hydrogens attached to the nitrogen are replaced by methyl groups. A histamine H1 antagonist, it is used to relieve the symptoms of hay fever, rhinitis, urticaria, and asthma.

Chlorpheniramine: A histamine H1 antagonist used in allergic reactions, hay fever, rhinitis, urticaria, and asthma. It has also been used in veterinary applications. One of the most widely used of the classical antihistaminics, it generally causes less drowsiness and sedation than PROMETHAZINE.
monochlorobenzenes;
pyridines;
tertiary amino compound
anti-allergic agent;
antidepressant;
antipruritic drug;
H1-receptor antagonist;
histamine antagonist;
serotonin uptake inhibitor
disulfiramorganic disulfide;
organosulfur acaricide
angiogenesis inhibitor;
antineoplastic agent;
apoptosis inducer;
EC 1.2.1.3 [aldehyde dehydrogenase (NAD(+))] inhibitor;
EC 3.1.1.1 (carboxylesterase) inhibitor;
EC 3.1.1.8 (cholinesterase) inhibitor;
EC 5.99.1.2 (DNA topoisomerase) inhibitor;
ferroptosis inducer;
fungicide;
NF-kappaB inhibitor
fluorescitefluorescein (acid form) : A xanthene dye that is highly fluorescent and commonly used as a fluorescent tracer.benzoic acids;
cyclic ketone;
hydroxy monocarboxylic acid;
organic heterotricyclic compound;
phenols;
xanthene dye
fluorescent dye;
radioopaque medium
maprotilineMaprotiline: A bridged-ring tetracyclic antidepressant that is both mechanistically and functionally similar to the tricyclic antidepressants, including side effects associated with its use.anthracenes
oxybutyninoxybutynin : A racemate comprising equimolar amounts of (R)-oxybutynin and esoxybutynin. An antispasmodic used for the treatment of overactive bladder.

oxybutynin: RN given refers to parent cpd
acetylenic compound;
carboxylic ester;
racemate;
tertiary alcohol;
tertiary amino compound
antispasmodic drug;
calcium channel blocker;
local anaesthetic;
muscarinic antagonist;
muscle relaxant;
parasympatholytic
pentamidinepentamidine : A diether consisting of pentane-1,5-diol in which both hydroxyl hydrogens have been replaced by 4-amidinophenyl groups. A trypanocidal drug that is used for treatment of cutaneous leishmaniasis and Chagas disease.

Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of PNEUMOCYSTIS pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic effects.
aromatic ether;
carboxamidine;
diether
anti-inflammatory agent;
antifungal agent;
calmodulin antagonist;
chemokine receptor 5 antagonist;
EC 2.3.1.48 (histone acetyltransferase) inhibitor;
NMDA receptor antagonist;
S100 calcium-binding protein B inhibitor;
trypanocidal drug;
xenobiotic
saccharinsaccharin : A 1,2-benzisothiazole having a keto-group at the 3-position and two oxo substituents at the 1-position. It is used as an artificial sweetening agent.

Saccharin: Flavoring agent and non-nutritive sweetener.
1,2-benzisothiazole;
N-sulfonylcarboxamide
environmental contaminant;
sweetening agent;
xenobiotic
sulfathiazolesulfathiazole : A 1,3-thiazole compound having a 4-aminobenzenesulfonamido group at the 2-position.

Sulfathiazole: A sulfathiazole compound that is used as a short-acting anti-infective agent. It is no longer commonly used systemically due to its toxicity, but may still be applied topically in combination with other drugs for the treatment of vaginal and skin infections, and is still used in veterinary medicine.
1,3-thiazoles;
substituted aniline;
sulfonamide;
sulfonamide antibiotic
antiinfective agent;
drug allergen;
EC 2.5.1.15 (dihydropteroate synthase) inhibitor;
environmental contaminant;
xenobiotic
suraminsuramin : A member of the class of phenylureas that is urea in which each of the amino groups has been substituted by a 3-({2-methyl-5-[(4,6,8-trisulfo-1-naphthyl)carbamoyl]phenyl}carbamoyl)phenyl group. An activator of both the rabbit skeletal muscle RyR1 and sheep cardiac RyR2 isoform ryanodine receptor channels, it has been used for the treatment of human African trypanosomiasis for over 100 years.

Suramin: A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties.
naphthalenesulfonic acid;
phenylureas;
secondary carboxamide
angiogenesis inhibitor;
antinematodal drug;
antineoplastic agent;
apoptosis inhibitor;
EC 2.7.11.13 (protein kinase C) inhibitor;
GABA antagonist;
GABA-gated chloride channel antagonist;
purinergic receptor P2 antagonist;
ryanodine receptor agonist;
trypanocidal drug
thiramthiram : An organic disulfide that results from the formal oxidative dimerisation of N,N-dimethyldithiocarbamic acid. It is widely used as a fungicidal seed treatment.

Thiram: A dithiocarbamate chemical, used commercially in the rubber processing industry and as a fungicide. In vivo studies indicate that it inactivates the enzyme GLUTATHIONE REDUCTASE. It has mutagenic activity and may induce chromosomal aberrations.
organic disulfideantibacterial drug;
antifungal agrochemical;
antiseptic drug
alizarindihydroxyanthraquinonechromophore;
dye;
plant metabolite
7-amino-4-hydroxy-2-naphthalenesulfonic acid7-amino-4-hydroxy-2-naphthalenesulfonic acid : An aminonaphthalenesulfonic acid that is 2-naphthalenesulfonic acid substituted by an amino group at position 7 and a hydroxy group at position 4 respectively.

7-amino-4-hydroxy-2-naphthalenesulfonic acid: structure given in first source
aminonaphthalenesulfonic acid;
naphthols
metabolite
1-naphthol-8-amino-3,6-disulfonic acid1-naphthol-8-amino-3,6-disulfonic acid: dye and found in industrial waste
methyl redmethyl red : An azo dye consisting of benzoic acid substituted at position 2 by a 4-[(dimethylamino)phenyl]diazenyl group.

methyl red: RN given refers to parent cpd; structure
1-deoxynojirimycin1-deoxy-nojirimycin: structure in first source

duvoglustat : An optically active form of 2-(hydroxymethyl)piperidine-3,4,5-triol having 2R,3R,4R,5S-configuration.
2-(hydroxymethyl)piperidine-3,4,5-triol;
piperidine alkaloid
anti-HIV agent;
anti-obesity agent;
bacterial metabolite;
EC 3.2.1.20 (alpha-glucosidase) inhibitor;
hepatoprotective agent;
hypoglycemic agent;
plant metabolite
s-adenosylmethionineacylcarnitine: structure in first source

S-adenosyl-L-methioninate : A sulfonium betaine that is a conjugate base of S-adenosyl-L-methionine obtained by the deprotonation of the carboxy group.
sulfonium betainehuman metabolite
miglustatmiglustat : A hydroxypiperidine that is deoxynojirimycin in which the amino hydrogen is replaced by a butyl group.

miglustat: a glucosylceramide synthase inhibitor
piperidines;
tertiary amino compound
anti-HIV agent;
EC 2.4.1.80 (ceramide glucosyltransferase) inhibitor
hexamidinehexamidine : A polyether that is the bis(4-guanidinophenyl) ether of hexane-1,6-diol.aromatic ether;
guanidines;
polyether
antimicrobial agent;
antiseptic drug
sinefunginadenosines;
non-proteinogenic alpha-amino acid
antifungal agent;
antimicrobial agent
fluorone blackfluorone Black: structure
c.i. direct red 23C.I. Direct Red 23: azo dye; structure in first source
mor-14N-methyldeoxynojirimycin: glucosidase inhibitorhydroxypiperidine;
piperidine alkaloid;
tertiary amino compound
anti-HIV agent;
cardioprotective agent;
EC 3.2.1.20 (alpha-glucosidase) inhibitor;
plant metabolite
furamidinefuramidine: RN given refers to parent cpd; WR 199385 refers to di-HCl; pafuramidine is a prodrug of this
homonojirimycinhomonojirimycin: inhibits alpha-glucosidase; RN given for (2R-(2alpha,3alpha,4beta,5alpha,6beta))-isomer; structure in first source
s-adenosylhomocysteineS-adenosyl-L-homocysteine : An organic sulfide that is the S-adenosyl derivative of L-homocysteine.

S-Adenosylhomocysteine: 5'-S-(3-Amino-3-carboxypropyl)-5'-thioadenosine. Formed from S-adenosylmethionine after transmethylation reactions.
adenosines;
amino acid zwitterion;
homocysteine derivative;
homocysteines;
organic sulfide
cofactor;
EC 2.1.1.72 [site-specific DNA-methyltransferase (adenine-specific)] inhibitor;
EC 2.1.1.79 (cyclopropane-fatty-acyl-phospholipid synthase) inhibitor;
epitope;
fundamental metabolite
n-nonyl-1-deoxynojirimycinN-nonyldeoxynojirimycin : A hydroxypiperidine that is deoxynojirimycin (duvoglustat) in which the amino hydrogen is replaced by a nonyl group.hydroxypiperidine;
tertiary amino compound
antiviral agent;
EC 3.2.1.20 (alpha-glucosidase) inhibitor;
EC 3.2.1.45 (glucosylceramidase) inhibitor
cefsulodincefsulodin : A pyridinium-substituted semi-synthetic, broad-spectrum, cephalosporin antibiotic.

Cefsulodin: A pyridinium-substituted semisynthetic, broad-spectrum antibacterial used especially for Pseudomonas infections in debilitated patients.
cephalosporin;
organosulfonic acid;
primary carboxamide
antibacterial drug
stilbamidinestilbamidine: RN given refers to parent cpd
mbx 1090
somatostatinheterodetic cyclic peptide;
peptide hormone
(5-bromo-3-pyridinyl)-[4-(1-pyrrolidinyl)-1-piperidinyl]methanonearomatic carboxylic acid;
pyridinemonocarboxylic acid
entecavirbenzamides;
N-acylpiperidine
gsk343GSK343 : A member of the class of indazoles that is 1-isopropyl-1H-indazole-4-carboxamide in which the nitrogen of the carboxamide group is substituted by a (6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl group and in which the indazole ring is substituted at position 6 by a 2-(4-methylpiperazin-1-yl)pyridin-4-yl group. A highly potent and selective EZH2 inhibitor (IC50 = 4 nM).

GSK343: an EZH2 methyltransferase inhibitor
aminopyridine;
indazoles;
N-alkylpiperazine;
N-arylpiperazine;
pyridone;
secondary carboxamide
antineoplastic agent;
apoptosis inducer;
EC 2.1.1.43 (enhancer of zeste homolog 2) inhibitor
6,7-dimethoxy-2-(pyrrolidin-1-yl)-n-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine: a SETD8 inhibitor; structure in first source