Mechanobiology Gene Review Project

SCOPING BIOLOGY_DOMAINFLAGSHIP

Species: human

Mechanobiology Gene Review Project

Bottom line: cells sense stiffness, shear, stretch, compression and
membrane tension through channels such as PIEZO1, integrin adhesions, the
nuclear lamina and the YAP/TAZ pathway, and GO annotations in this area mix
genuine sensors with generic adhesion, cytoskeleton and ECM terms. This page
defines the scope for reviewing that gene set: inclusion criteria, six
sensor-to-modifier modules, 30 candidate genes in five review batches, and
the stimulus -> sensor -> downstream axis -> phenotype chain each review
should record. We scoped it this way so that reviews separate the few direct
mechanosensors from the many downstream effectors and ECM genes that are easy
to over-annotate with response to mechanical stimulus. Scoped, not yet
started: none of the Batch A to D genes (PIEZO1/2, TRPV4, PKD1/2, the
integrin adhesome, LINC complex or Hippo effectors) has a review in the repo.
Four Batch E matrix genes (FN1, LOX, SPARC, DCN) have human reviews made for
other purposes, covering 355 annotations, but none has been assessed against
this project's mechanical-chain questions.

Scope

This project reviews genes whose core function is to sense mechanical cues, transmit force-dependent signals, or reshape the mechanical microenvironment in ways that drive reproducible biological outcomes.

This scaffold was informed by cmungall/stuff#671, but the project stays deliberately narrower and more practical than the grant-style framing in that issue:
- focus on reviewable genes, evidence-backed mechanisms, and curation outputs
- use disease relevance to prioritize batches, not to over-claim translational impact
- treat ontology or knowledge-graph follow-up as optional downstream outputs, not the primary deliverable

Operationally, each reviewed gene should be placed in a concrete chain:

mechanical stimulus -> sensor/transducer -> downstream axis -> phenotype/context

Practical inclusion criteria

Include genes when there is evidence for one or more of the following:
- direct sensing of membrane tension, stretch, shear, compression, or osmotic/mechano-osmotic change
- force transmission through adhesions, cortex, cytoskeleton, primary cilium, or nucleus
- robust mechanosensitive downstream signaling repeatedly tied to defined mechanical contexts
- active remodeling of ECM stiffness/compliance or tissue mechanics that is central to the gene's biological role

Deprioritize genes when they are only:
- generic proliferation, migration, or stress-response genes without a defined mechanical trigger
- broad ECM structural components with no mechanotransduction-specific evidence
- one-off assay hits from poorly defined stretching/stiffness systems

Mechanical stimulus space to capture explicitly

Candidate mechanosensor and transduction modules

1. Direct or near-direct mechanical sensors

2. Adhesion and focal-adhesion force coupling

3. Cytoskeletal force transmission

4. Nuclear mechanotransmission

5. Downstream mechanosensitive effectors

6. Mechanical microenvironment modifiers

Suggested first review batches

Batch A: canonical direct mechanosensors

Batch B: integrin-adhesome force transduction

Batch C: nucleus-cytoskeleton coupling

Batch D: downstream mechanical state effectors

Batch E: matrix stiffening and fibrosis anchor genes

Downstream axes to record in reviews

When a gene is in scope, reviewers should try to capture which of these axes is actually supported:
- Ca2+ influx and ion-channel signaling
- RhoA/ROCK-actomyosin contractility
- Hippo/YAP/TAZ nuclear localization or transcriptional output
- FAK/Src/MAPK signaling
- mTOR / growth-state coupling
- TGF-beta / SMAD fibrotic remodeling
- Endothelial flow programs such as KLF2/KLF4/NOS3
- Migration / invasion / EMT-like programs when clearly tied to force context

Disease and tissue anchors for prioritization

These are useful anchors for choosing batches, but should not become hype-driven claims:
- Fibrosis: lung, liver, heart, kidney; matrix stiffening and feed-forward myofibroblast activation
- Cancer invasion and metastasis: confinement, adhesion turnover, ECM remodeling, YAP/TAZ programs
- Cardiovascular and endothelial biology: shear stress, stretch, cardiac remodeling
- Kidney and cilia-linked mechanosensation: flow detection and tubular phenotypes
- Cartilage, bone, tendon, and muscle: load-bearing mechanobiology

Expected outputs

Questions to keep asking during curation

Guardrails

How issue #671 influenced this framing

The issue materially improved the scaffold in four ways:

  1. It expanded the project from a narrow ECM/stiffness idea into a fuller mechanical landscape including shear, tension, compression, membrane tension, and osmotic pressure.
  2. It surfaced a practical shortlist of mechanobiology anchor classes: Piezo channels, integrin/adhesion machinery, nuclear lamins, and YAP/TAZ-linked signaling.
  3. It pushed the framing toward explicit stimulus -> sensor -> downstream phenotype chains rather than a flat list of "mechanics-related genes."
  4. It suggested useful disease anchors and outputs, especially fibrosis, cancer invasion, and cardiovascular remodeling.

What was intentionally not adopted from the issue as a primary goal:
- a new mechanobiology ontology
- a large AI extraction platform
- broad therapeutic-discovery claims

Those may become relevant later, but the present project is first a grounded curation and synthesis effort for ai-gene-review.

Source input

Slides