Biological complexity: controls over red cell manufacture (Introduction)

by David Turell , Friday, May 14, 2021, 19:48 (1077 days ago) @ David Turell

As usual very complex with specific molecules driving the process:

https://science.sciencemag.org/content/372/6543/716

"Metabolic pathway regulates cell fate
Lineage-specific regulators direct cell fate decisions, but the precise mechanisms are not well known. Using an in vivo chemical suppressor screen of a bloodless zebrafish mutant, Rossmann et al. show that the lineage-specific chromatin factor tif1γ directly regulates mitochondrial genes to drive red blood cell differentiation. Loss of tif1γ reduces coenzyme Q synthesis and function, impeding mitochondrial respiration and leading to epigenetic alterations and repression of erythropoiesis. The loss of blood in the mutant fish can be rescued by the addition of coenzyme Q. This work establishes a mechanism by which a chromatin factor tunes a metabolic pathway in a tissue-specific manner.

"Abstract
Transcription and metabolism both influence cell function, but dedicated transcriptional control of metabolic pathways that regulate cell fate has rarely been defined. We discovered, using a chemical suppressor screen, that inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) rescues erythroid differentiation in bloodless zebrafish moonshine (mon) mutant embryos defective for transcriptional intermediary factor 1 gamma (tif1γ). This rescue depends on the functional link of DHODH to mitochondrial respiration. The transcription elongation factor TIF1γ directly controls coenzyme Q (CoQ) synthesis gene expression. Upon tif1γ loss, CoQ levels are reduced, and a high succinate/α-ketoglutarate ratio leads to increased histone methylation. A CoQ analog rescues mon’s bloodless phenotype. These results demonstrate that mitochondrial metabolism is a key output of a lineage transcription factor that drives cell fate decisions in the early blood lineage.

"Vertebrate embryos produce circulating red blood cells (RBCs) that are required for oxygen and carbon dioxide transport. During embryonic development, three overlapping hematopoietic waves can be distinguished that all produce RBCs. In mammals, primitive erythroblasts that emerge in the blood islands within the extraembryonic yolk sac give rise to primitive erythrocytes of the first transient wave, and a second wave generates definitive erythroid-myeloid progenitors in the hemogenic endothelium of the yolk sac. Definitive erythrocytes of the third wave arise from multipotent hematopoietic stem cells that are born in the aortic endothelium of the aorta-gonad-mesonephros region and sustain hematopoiesis throughout the lifetime of the animal. Primitive erythrocytes supply the embryo with the oxygen needed for its rapid proliferation. Failure to initiate the first wave of erythropoiesis leads to embryonic lethality. Erythroid lineage differentiation is regulated by key transcription factors, but the cellular mechanisms that allow the generation and differentiation of the first erythroid progenitors remain largely unknown. Stem and descendent progenitor cells differ by their metabolic profiles, but there is little in vivo evidence for a link between transcriptional regulation and metabolic changes during cell fate decisions.

***

"Discussion
Tissue differentiation can be regulated by metabolic activities. It was previously unclear how lineage transcription factors induce distinct changes during cell fate specification and lineage differentiation. Our work demonstrates that the metabolic state of the tissue required for early erythroid lineage differentiation is under the direct transcriptional control of TIF1γ. CoQ is a critical downstream effector of TIF1γ transcriptional activity, regulating the balance between nucleotide synthesis and ETC activity in embryonic erythropoiesis. This highlights a previously unappreciated role of mitochondrial respiration in driving the early commitment of the erythroid lineage. It has been proposed that transcriptional and metabolic processes influence each other. We demonstrate that this is the case in early erythropoiesis, where exogenous CoQ can drive erythroid differentiation in the mon mutant, including the expression of embryonic globin as a late lineage marker."

comment: this highly complex research article describes the surface of the controlling molecules. We see what controls what, but not how the controls are really performed. This is the magic of the unseen, but understood to exist, exotic control systems that controls/creates embryology and all of life. It is only by understanding this hidden layer exists and must be of the highest complexity, everyone should then understand a designing mind has to be the source. Can research get to this level and reveal it? I hope so. But one shouldn't have to wait for explicit descriptions of the process to accept a designing mind.