A Computational Approach for Mapping Heme Biology in the Context of Hemolytic Disorders

Abstract

Heme is an iron ion-containing molecule found within hemoproteins such as hemoglobin and cytochromes that participates in diverse biological processes. Although excessive heme has been implicated in several diseases including malaria, sepsis, ischemiareperfusion, and disseminated intravascular coagulation, little is known about its regulatory and signaling functions. Furthermore, the limited understanding of heme's role in regulatory and signaling functions is in part due to the lack of curated pathway resources for heme cell biology. Here, we present two resources aimed to exploit this unexplored information to model heme biology. The first resource is a terminology covering heme-specific terms not yet included in standard controlled vocabularies. Using this terminology, we curated and modeled the second resource, a mechanistic knowledge graph representing the heme's interactome based on a corpus of 46 scientific articles. Finally, we demonstrated the utility of these resources by investigating the role of heme in the Toll-like receptor signaling pathway. Our analysis proposed a series of crosstalk events that could explain the role of heme in activating the TLR4 signaling pathway. In summary, the presented work opens the door to the scientific community for exploring the published knowledge on heme biology.

Unravelling the debate on heme effects in COVID-19 infections

“…In order to investigate the mechanisms linking SARS-CoV-2 and heme, we exploited the KGs generated in our previous work Humayun et al, 2020). We compiled the two KGs encoded in Biological Expression Language (BEL) using PyBEL (Hoyt et al, 2018) directly from their public repositories (i.e.…”

“…Overall, these clinical parameters are interrelated when viewed from the perspective of heme and its interaction radius (Dutra and Bozza, 2014;Kühl and Imhof, 2014;Roumenina et al, 2016;Humayun et al, 2020). Heme is well-known as the prosthetic group of diverse proteins, e.g., hemoglobin, where it is responsible for the oxygen transport in the blood (Ascenzi et al, 2005).…”

“…In addition, for heme a downstream ROS-dependent induction of distinct signaling pathways (MAPK/ERK pathway, NFκB signaling) is discussed, which can lead to stimulation of neutrophil recruitment, necrotic cell death or expression of adhesion molecules (Dutra and Bozza, 2014). In fact, we recently contextualized the role of heme as an inflammatory mediator as well as its crosstalk with the TLR4 signaling pathway (Humayun et al, 2020). Although the aforementioned findings suggest a connection between biological processes implicated in SARS-CoV-2 and those related to heme, the lack of information on both subject areas impedes the use of modeling approaches that can facilitate their interpretation.…”

“…Likewise, data in the context of heme's biology is underrepresented, if available at all, in standard bioinformatics resources such as pathway databases. However, two of our recent scientific publications have focused on modeling knowledge around heme as well as SARS-CoV-2 Humayun et al, 2020). Although both studies are tangential, each follows a knowledge-driven approach aimed at generating a context-specific Knowledge Graph (KG) that can subsequently be employed to investigate candidate mechanisms involved in hemolytic disorders and COVID-19.…”

“…On the other hand, by superimposing the two knowledge graphs, i.e. heme KG (Humayun et al, 2020) and COVID-19 KG (Domingo-Fernández et al, 2020), we provide insights into pathways that might play a role when considering heme in the context of COVID-19 infections.…”