PROJECTS

Human Steroidogenesis

The human adrenal cortex synthesizes steroid hormones including glucocorticoids, mineralocorticoids, and androgens. Defects resulting in either under- or over-production of these steroid hormones are pathological. For example, over-production of aldosterone is responsible for ~%10 of hypertensive individuals. Our goal is to achieve a quantitative understanding of the dynamic molecular mechanisms regulating steroidogenesis. Ultimately, we hope to precisely modulate hormone production through potentiating or inhibiting RNA regulatory interactions. These approaches could have important implications for patients with adrenal disease.

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Ongoing projects in the lab focus on:
  1. The RNA regulatory dynamics underlying steroid production.
    • How do RNA decay rates and changes in RNA decay rates coordinate steroidogenic gene expression kinetics?
  2. The molecular mechanism of trans-acting regulatory factors controlling steroidogenesis, specifically:
    • RNA-binding proteins (RBPs)
    • RNA modifications (psuedoridylation)
    •  non-coding RNAs (including snRNAs and lncRNAs)

RBPs?

lncRNAs?

RNA regulatory dynamics

On the left is a time-course RNA-seq experiment of adrenocortical cells stimulated with AngII. We identified 12 regulatory modules with distinct temporal responses. The decay rates of RNAs in the regulatory modules were inversely proportional to the time to peak response. We also found evidence for increases in RNA decay of many transcriptionally activated RNAs encoding pro-steroidogenic factors.

RNA regulatory factors

RNA-binding proteins

Through siRNA screening, we have identified numerous RBP that control hormone production. Our goal is to understand the dynamic RBP-RNA regulatory network controlling steroidogenesis.

 

Long non-coding RNA

We have also identified a lncRNA that regulates steroidogenesis and are currently investigating the molecular mechanism.

Regulatory Motifs

Our research indicates that coordination between transcription and decay temporally coordinates the expression kinetics of the regulatory modules important for steroid biosynthesis. On the left is one example we think is important to prevent the overproduction of aldosterone. AngII activates the transcription of pro-steroidogenic transcripts, while simultaneously activating the transcription of mRNA decay factors that repress pro-steroidogenic mRNAs by increasing their turnover.  These regulatory architectures have very interesting emergent properties that would be important for steroid hormone homeostasis.