Human Cells and Genomics on Medicine

Single-cell atlases promise to provide a ‘missing link’ between genes, diseases and therapies. By identifying the specific cell types, states, programs and contexts where disease-implicated genes act, we will understand the mechanisms of disease at the cellular and tissue levels and can use this understanding to develop powerful disease diagnostics; identify promising new drug targets; predict their efficacy, toxicity and resistance mechanisms; and empower new kinds of therapies, from cancer therapies to regenerative medicine. Here, we lay out a vision for the potential of cell atlases to impact the future of medicine, and describe how advances over the past decade have begun to realize this potential in common complex diseases, infectious diseases (including COVID-19), rare diseases and cancer.

im very optimistic on cell atlases to impact the future of medicine.

first draft of the human pangenome reference

https://www.nature.com/articles/s41586-023-05896-x

  • A new organelle (PXo) inside the gut cells of Drosophila melanogaster (common fruit fly) was discovered
  • PXo specifically marks non-canonical multilamellar organelles (PXo bodies)
  • PXo bodies as a critical regulator of cytosolic Pi levels

image

https://www.nature.com/articles/s41586-023-06039-y

Studies of Two species ( Downy (D. pubescens ) and Hairy Woodpeckers (D. villosus )) that codistributed across a heterogeneous environmental gradient in North America showed:

  • Despite the large evolutionary distance between the species, natural selection targeted convergent genetic mechanisms for local adaptation.
  • Genotype-environment analysis identified SNP windows strongly associated with temperature and precipitation, indicating selective pressures from climatic variables.
  • Several candidate genes exhibited signatures of natural selection in both Downy and Hairy Woodpeckers, related to processes such as embryonic development, nutritional metabolism, mitochondrial respiration, and oxygen transportation.
  • Shared candidate genes were associated with DNA replication, immune response, and defense against region-specific pathogens.
  • Convergent signatures of selection in genes related to the IGF signaling pathway were consistent with differences in body size among population comparisons.
  • These findings suggest that adaptation to environmental variation is often achieved through common genetic pathways, even in species that have diverged for over eight million years.

Convergent genomic signatures of local adaptation across a continental-scale environmental gradient https://www.science.org/doi/10.1126/sciadv.add0560

  1. Brain and dorsal root ganglia-expressed FAAH-OUT long non-coding RNA (lncRNA) gene was found from studying a pain-insensitive patient with reduced anxiety and fast wound healing. ----- Habib AM, Okorokov AL, Hill MN, et al. Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. Br J Anaesth. 2019;123:e249–e253.
  2. It regulates the adjacent key endocannabinoid system gene FAAH , which encodes the anandamide-degrading fatty acid amide hydrolase enzyme.
  3. The disruption in FAAH-OUT lncRNA transcription leads to DNMT1-dependent DNA methylation within the FAAH promoter.
  4. FAAH-OUT contains a conserved regulatory element, FAAH-AMP, that acts as an enhancer for FAAH expression.
  1. Inhibitory killer cell immunoglobulin-like receptors (iKIRs) have been shown to modulate T cell responses in transgenic mice and in vitro.
  2. iKIRs are an important determinant of T cell-mediated control of chronic viral infection.
  3. The interaction between iKIRs and their ligands increases the lifespan of CD8+ T cells.
  4. Individuals with 2 iKIR-ligand gene pairs had memory CD8+ T cells surviving for an average of 125 days.
  5. Individuals with 4 iKIR-ligand gene pairs had the lifespan of memory CD8+ T cells doubled to 250 days.
  6. The survival advantage conferred by iKIR-ligand genotype was independent of iKIR expression by the T cell.
  7. The iKIR-ligand genotype also affected the immune aging phenotype of CD8+ and CD4+ T cells.

https://www.jci.org/articles/view/169496

  1. Hair follicle stem cells (SCs) in the bulge exhibit stiffness and high actomyosin contractility.
  2. Hair germ (HG) progenitors are soft and undergo periodic enlargement and contraction during quiescence.
  3. During hair follicle growth activation, HGs reduce contraction and more frequently enlarge.
  4. Induction of miR-205, a regulator of the actomyosin cytoskeleton, reduces actomyosin contractility.
  5. Activation of hair regeneration is observed in both young and old mice.
  6. The study highlights the control of tissue SC size and activities by compartmentalized mechanical properties.
  7. Fine-tuning cell mechanics shows potential for stimulating tissue regeneration.

MicroRNA-205 promotes hair regeneration by modulating mechanical properties of hair follicle stem cells | PNAS

Multiple approaches of cellular metabolism define the bacterial ancestry of mitochondria

  1. Mitochondria and Cellular Energy Production:
  • Mitochondria consume oxygen to extract energy from nutrients at the molecular level.
  1. Mitochondrial Origin and Characteristics:
  • Mitochondria are organelles derived from aerobic bacteria. They perform oxidative phosphorylation and essential metabolic pathways in eukaryotic cells.
  1. Controversy Regarding Bacterial Origin:
  • Despite extensive genomic information, the exact bacterial origin of mitochondria is still disputed.
  1. Preferred Environment of Ancestral Bacteria:
  • The ancestral bacteria are found in marine environments.
    • The identified bacteria possess a high frequency of aerobic traits. These bacteria also carry genes related to the metabolism of fundamental lipids.
  1. Specific Lipids in Eukaryotic Membranes:
  • The fundamental lipids found in eukaryotic membranes are sphingolipids and cardiolipin.
  1. Significance of Bacterial Characteristics:
  • The characteristics of the identified bacteria suggest a potential link to the ancestral bacteria that gave rise to mitochondria.

A study on the engraftment of the airway epithelial stem cell compartment via intra-airway transplantation of mouse or human primary and pluripotent stem cell (PSC)-derived airway basal cells (BCs). Results showed that murine primary or PSC-derived BCs transplanted into polidocanol-injured syngeneic recipients give rise for at least two years to progeny that stably display the morphologic, molecular, and functional phenotypes of airway epithelia. The engrafted basal-like cells retain extensive self-renewal potential, evident by the capacity to reconstitute the tracheal epithelium through seven generations of secondary transplantation. Using the same approach, human primary or PSC-derived BCs transplanted into NOD scid gamma (NSG) recipient mice similarly display multilineage airway epithelial differentiation in vivo.

https://www.sciencedirect.com/science/article/pii/S1934590923002813?via%3Dihub

  • A new method involves temporally multiplexed imaging (TMI) using genetically encoded fluorescent proteins to study signal transduction cascades in living systems.
  • Different clocklike properties of fluorescent proteins, such as reversibly photoswitchable ones with different switching kinetics, are utilized.
  • TMI allows the imaging of multiple signals simultaneously in the same living cell using standard microscopes.
  • A linear decomposition approach is applied to analyze fluorescence fluctuations in a brief trace, representing different cellular signals.
  • The weights obtained from the decomposition represent the signal amplitudes of each fluorophore expressed in the cell.
  • TMI is employed to analyze relationships between kinase activities in individual cells and different cell-cycle signals.

Cell. 2023 Dec 7;186(25):5656-5672.e21.

DOI:Redirecting