Date Approved

8-2022

Document Type

Dissertation

Degree Name

PhD in Cell and Molecular Biology

Department

Molecular Biology

College

Graduate School of Biomedical Sciences, Virtua Health College of Medicine and Life Sciences of Rowan University

First Advisor

Eric Moss, PhD

Committee Member 1

Ronald Ellis, PhD

Committee Member 2

Susan Muller-Weeks, PhD

Committee Member 3

Michael Henry, PhD

Committee Member 4

Hristo Houbaviy, PhD

Subject(s)

Caenorhabditis elegans, Ikaros Transcription Factor, Transcription Factors, Gene Expression Regulation

Disciplines

Cell Biology | Genetic Processes | Laboratory and Basic Science Research | Medical Cell Biology | Medicine and Health Sciences | Molecular Biology | Molecular Genetics

Abstract

In Caenorhabditis elegans, the heterochronic pathway is comprised of a hierarchy of genes that control the proper timing of developmental events. hbl-1 (Hunchback Like-1) encodes an Ikaros family zinc-finger transcription factor that promotes the L2 stage cell fate events of the hypodermis. The downregulation ofhbl-1 is a crucial step for the transition from the L2 to the L3 stage. There are two known processes through which negative regulation of hbl-1 occurs: suppression of hbl-1 expression by 3 let-7 miRNAs through the hbl-1 3’UTR and inhibition of HBL-1 activity by LIN-46. The mechanisms by which hbl-1 is positively regulated have not yet been full defined. Currently, this positive regulation seems to be the responsibility of the conserved developmental regulator lin-28. lin-28 is purported to oppose the activities of the 3 let-7 miRNAs and the Caenorhabditis specific heterochronic gene lin-46. Here I demonstrate the removal of 3 let-7 miRNA binding sites in 3’UTR of hbl-1 does not abolish negative regulation of hbl-1 in seam cells. I find lin-28 negatively regulates lin-46 expression by direct binding of the 5’UTR of lin-46. I report a novel sterilely phenotype due to the loss of HBL-1 activity in postembryonic development. Due to the increased sensitivity of the somatic gonad to HBL-1 protein levels, I utilize the development of this tissue as an alternate means to study the genetic relationships between lin-28, lin-46 and hbl-1. My results suggest lin-28 acts through a branched pathway, partially bypassing lin-46 to positively regulate hbl-1 either through its 3’UTR or by targeting a third unknown factor.

Download

Share

COinS