What is Epigenetics and Why should we care?

You must of heard scientists always saying that every cell in your body has the same DNA or genetic make-up. Have you ever wondered why you would have over 200 different cell types within your body, after all they all have the same DNA? Nevertheless, humans have neurons that transmit signals from brain to other organs, myocardiocytes in the heart that contract and help to pump the blood, just to name a few. So there’s something in addition to the DNA code that dictates all those functions and that is epi-genetics (“epi-” prefix comes from Greek and means upon, over).

Emerging Epigenetic Therapies

Epigenetics in itself as a field is new and there are relatively low number of FDA approved epigenetic therapeutics found on the market. Majority of these drugs are for oncology indication, but we strongly believe that therapeutics against epigenetic targets can be efficacious and safe outside of the oncology space.

Viral Epigenetics

Epigenetic regulation occurs during the course of a viral infection. For example, SARS-CoV2 entry into lung cells depends on the levels of ACE2 and TMPRSS2 protein. Also, increased expression of ACE2 in the lungs of patients with comorbidities has been correlated with more severe COVID-19 symptoms. Although limited work has been done, but gene network analysis implicated epigenetic enzymes such as histone acetyltransferase 1 (HAT1), histone deacetylase 2 (HDAC2) and lysine demethylase 5B (KDM5B) in regulating ACE2 expression.

Additionally, nucleocapsin protein in SARS-CoV2 – that plays critical role in packaging the viral genome, so the virus can function and spread more efficiently – has been shown to be acetylated by p300/CBP-associated factor (PCAF or KAT2B) and general control nonderepressible 5 (GCN5 or KAT2A) in vitro. This acetylation was shown to be important for the proper function of nucleocapsin protein.

Lastly, a number of genome-wide CRISPR screens have been performed and identified proteins required for SARS-CoV2 entry into the cells. ACE2 comes up as a hit, which validates our idea that targeting factors that regulate ACE2 expression could be of therapeutic value. Of course, there’s a long list of other factors also, which we are in the process of validating now. This issue of Cell contains a number of such screens.

References:

Hoffmann et al. Cell, 2020 Apr 16; 181(2): 271–280.e8. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Pinto et al., Version 1. medRxiv, Preprint. 2020 Mar 27. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19

Hatakeyama et al. Biocem Biophys Res Commun. 2021 Apr 8;557:273-279. In-vitro acetylation of SARS-CoV and SARS-CoV-2 nucleocapsid proteins by human PCAF and GCN5

CRISPR-based screens

Our Pipeline

We are an early-stage start-up company interested in establishing collaborations to support our current growing pipeline:

	In Vitro Screening	In Vivo Validation	Phase I	Phase II	Phase III
HAT1	X
KAT2A/2B	X
HDAC2	X
KDM5B	X
undisclosed	X