# The role of ASARs in chromosome dynamics

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $308,000

## Abstract

Summary/Abstract
Mammalian cells initiate DNA replication at multiple sites along each chromosome at different times, following
a temporal replication program. We have used a chromosome-engineering strategy to identify cis-acting loci
that control this replication-timing program on individual human chromosomes. We found that Cre/loxP-
mediated translocations, affecting eight different autosomes, display a delay in replication timing and structural
instability of entire chromosomes. Subsequently, we found that Cre/loxP-mediated disruption of the lncRNA
genes ASAR6 and ASAR15 result in delayed replication of human chromosomes 6 and 15, respectively.
ASAR6 and ASAR15 share numerous characteristics, including: 1) random mono-allelic expression of
lncRNAs that can physically “coat” entire chromosomes in cis; 2) asynchronous replication between alleles; 3)
genetic disruption results in structural instability of their respective chromosomes; and 4) ectopic integration of
transgenes causes delayed replication of entire chromosomes in cis. In earlier studies, we detected the
delayed replication and structural instability phenotypes following rearrangement of numerous human and
mouse chromosomes, suggesting that all mammalian chromosomes are regulated by similar mechanisms. Our
work suggests that all mammalian chromosomes are regulated by similar loci. Therefore, we are proposing
that all mammalian chromosomes contain “Inactivation/Stability Centers” (I/SCs), which normally function to
promote proper replication timing, monoallelic gene expression and structural stability of individual
chromosomes. We believe that I/SCs are as fundamentally important to mammalian chromosome biology as
telomeres, centromeres, or origins of replication. Thus, under this scenario every mammalian chromosome
contains four essential cis-acting elements, origins, centromeres, telomeres, and I/SCs all functioning to
ensure proper replication, segregation and stability of each chromosome. This proposal is designed to
elucidate the mechanisms by which ASAR6 and ASAR15 RNAs control chromosome replication timing, to
identify chromatin interaction sites of ASAR6 and ASAR15 RNAs, and to determine the mechanisms by which
ASAR6 and ASAR15 function to localize chromosomes within the 3D space of the nucleus, and if they control
the genome interaction maps of chromosomes 6 and 15. If successful the experiments described in this
proposal will help to establish a new paradigm for mammalian chromosome biology, and will serve as the
foundation for a fourth type of essential chromosomal element, the “Inactivation/Stability Center”.

## Key facts

- **NIH application ID:** 9985952
- **Project number:** 5R01GM130703-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** MATHEW J THAYER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $308,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985952

## Citation

> US National Institutes of Health, RePORTER application 9985952, The role of ASARs in chromosome dynamics (5R01GM130703-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9985952. Licensed CC0.

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