Asymmetric Segregation of the Nucleosome Remodeling and Deacetylase Complex Determines Daughter Cell Fates in Caenorhabditis elegans

Core Concepts

The nucleosome remodeling and deacetylase (NuRD) complex is asymmetrically segregated into the surviving daughter cell during asymmetric cell divisions in Caenorhabditis elegans, determining the life-versus-death fate of the daughter cells.

Abstract

The study investigates the mechanisms underlying asymmetric cell division (ACD) in Caenorhabditis elegans, where two daughter cells with identical genetic information but distinct cell fates are generated. The authors demonstrate that the nucleosome remodeling and deacetylase (NuRD) complex is asymmetrically segregated into the surviving daughter cell rather than the apoptotic one during ACDs.
Key highlights:

The NuRD complex, which couples chromatin-remodeling ATPases with histone deacetylases, is enriched in cells that are predetermined to survive during ACDs.
Live imaging reveals that NuRD subunits HDA-1 and LIN-53 become asymmetrically distributed, with higher levels in the surviving daughter cell compared to the apoptotic one.
Inhibition of the NuRD complex triggers ectopic apoptosis through upregulation of the apoptosis-inducing gene egl-1, which requires the canonical apoptosis pathway.
The vacuolar H+-ATPase (V-ATPase) complex interacts with NuRD and is also asymmetrically segregated. Inhibition of V-ATPase disrupts the cytosolic pH asymmetry and NuRD asymmetry.
The authors propose that the asymmetric segregation of V-ATPase may cause distinct acidification levels in the two daughter cells, enabling asymmetric epigenetic inheritance that specifies their respective life-versus-death fates.

Stats

"The absence of NuRD triggers apoptosis via the EGL-1-CED-9-CED-4-CED-3 pathway."
"RNAi of hda-1 or lin-53 caused embryonic lethality."
"BafA1 treatment reduced the pHluorin fluorescence intensity ratio between QR.ap and QR.aa from 1.6-fold to 1.3-fold."
"In BafA1-treated animals, 11 out of 12 QR.aa cells carrying ectopic NuRD survived for over 120 min and formed a short neurite-like outgrowth."

Quotes

"Asymmetric cell division (ACD) gives rise to two daughter cells that possess identical genetic material but distinct cell fates, playing a crucial role in both development and tissue homeostasis."
"We suggest that asymmetric segregation of V-ATPase may cause distinct acidification levels in the two daughter cells, enabling asymmetric epigenetic inheritance that specifies their respective life-versus-death fates."
"Our findings provide new insights into the asymmetric segregation of cell-intrinsic factors and the previously unrecognized roles of V-ATPase and cytosolic acidification in this process."

Key Insights Distilled From

Vacuolar H+-ATPase Determines Daughter Cell Fates through Asymmetric Segregation of the Nucleosome Remodeling and Deacetylase Complex

by Xie,Z., Chai... at www.biorxiv.org 06-26-2023

https://www.biorxiv.org/content/10.1101/2023.06.25.546476v4

Deeper Inquiries

How might the asymmetric segregation of NuRD and V-ATPase be regulated in other developmental contexts beyond the Q neuroblast lineage in C. elegans?

In other developmental contexts beyond the Q neuroblast lineage in C. elegans, the asymmetric segregation of NuRD and V-ATPase could be regulated through similar mechanisms involving a combination of intrinsic and extrinsic factors.

Intrinsic Factors:

Cell Fate Determinants: Specific proteins or RNA molecules that act as cell fate determinants may play a role in guiding the asymmetric segregation of NuRD and V-ATPase. These determinants could be localized asymmetrically within the mother cell, influencing the distribution of epigenetic regulators during cell division.
Chromosomal Proteins: Chromosomal proteins or modifications on sister chromatids could provide cues for the asymmetric segregation of NuRD and V-ATPase. Differential recruitment of NuRD to chromatin regions based on chromosomal protein modifications could lead to asymmetric distribution.

Extrinsic Factors:

Signaling Pathways: External signaling cues from the microenvironment could influence the localization and segregation of NuRD and V-ATPase during cell division. Signaling pathways that regulate cell fate decisions may impact the asymmetric distribution of epigenetic regulators.
Cell Polarity: Cellular polarity cues, such as the establishment of apical-basal polarity or planar cell polarity, could contribute to the asymmetric segregation of NuRD and V-ATPase in different developmental contexts.

Organelle Dynamics:

Endoplasmic Reticulum (ER): As observed in the Q neuroblast lineage, the ER could play a role in the polarized distribution of NuRD and V-ATPase. The ER may serve as a platform for the assembly and transport of NuRD-V-ATPase-containing organelles to the daughter cells.
Microtubule Transportation System: A polarized microtubule transportation system, involving specific motor proteins and microtubule tracks, could selectively deliver NuRD-V-ATPase complexes to the appropriate daughter cell during cell division.

By considering these factors, researchers can explore how the asymmetric segregation of NuRD and V-ATPase is regulated in diverse developmental contexts, providing insights into cell fate determination mechanisms beyond the Q neuroblast lineage in C. elegans.

What are the potential implications of disrupting NuRD asymmetry for human health, such as in the context of cancer or neurodegenerative diseases?

Disrupting NuRD asymmetry could have significant implications for human health, particularly in the context of cancer and neurodegenerative diseases.

Cancer:

Tumor Development: Alterations in NuRD asymmetry could lead to dysregulation of gene expression patterns, potentially promoting tumor development and progression.
Therapeutic Resistance: Disruption of NuRD asymmetry may impact the sensitivity of cancer cells to therapies targeting epigenetic regulators, leading to therapeutic resistance.
Metastasis: Changes in NuRD asymmetry could influence the metastatic potential of cancer cells by affecting their ability to undergo epithelial-mesenchymal transition (EMT) or invade surrounding tissues.

Neurodegenerative Diseases:

Neuronal Dysfunction: Imbalance in NuRD asymmetry could contribute to neuronal dysfunction and degeneration in neurodegenerative diseases such as Alzheimer's or Parkinson's disease.
Epigenetic Dysregulation: Disruption of NuRD asymmetry may lead to aberrant epigenetic modifications in neurons, affecting gene expression profiles critical for neuronal survival and function.
Cell Death Pathways: Changes in NuRD asymmetry could impact apoptotic pathways in neurons, influencing cell death processes associated with neurodegeneration.

Understanding the role of NuRD asymmetry in disease pathogenesis could provide insights into novel therapeutic strategies targeting epigenetic regulators for cancer treatment and neurodegenerative disease management.

Could the principles of asymmetric segregation of epigenetic regulators be leveraged to engineer novel cell fate determination strategies in regenerative medicine or synthetic biology applications?

The principles of asymmetric segregation of epigenetic regulators offer exciting opportunities for engineering novel cell fate determination strategies in regenerative medicine and synthetic biology applications.

Regenerative Medicine:

Stem Cell Differentiation: By manipulating the asymmetric segregation of epigenetic regulators, researchers could enhance the differentiation of stem cells into specific cell lineages for tissue regeneration and repair.
Cell Reprogramming: Understanding the mechanisms of asymmetric segregation could aid in the development of more efficient cell reprogramming techniques, allowing for the generation of desired cell types for regenerative therapies.
Organoid Development: Leveraging asymmetric segregation principles could improve the generation of complex organoids with distinct cell populations, mimicking native tissue architecture for disease modeling and drug screening.

Synthetic Biology:

Cell Fate Engineering: Engineering asymmetric segregation pathways in synthetic biological systems could enable the precise control of cell fate decisions in engineered tissues or organisms.
Biological Circuits: Incorporating asymmetric segregation mechanisms into synthetic biological circuits could enhance the robustness and functionality of engineered systems for biotechnological applications.
Cellular Memory: Utilizing asymmetric segregation principles could facilitate the creation of cellular memory systems, allowing engineered cells to retain specific epigenetic states for prolonged periods.

By harnessing the principles of asymmetric segregation of epigenetic regulators, researchers can develop innovative strategies for cell fate determination in regenerative medicine and synthetic biology, opening up new possibilities for tissue engineering, disease modeling, and biotechnological advancements.