A National Cancer Institute-designated Comprehensive Cancer Center

Make an appointment: 800-826-HOPE
Singer-Sam, Judith, Ph.D. Laboratory Bookmark and Share

Laboratory of Judith Singer-Sam, Ph.D.

For a growing number of genes, only one of the two chromosomal copies (or alleles) is expressed, a phenomenon termed monoallelic expression. In some cases, there is random selection of the expressed allele; in others parental origin determines which allele is expressed, which is termed imprinting. Disorders with a genetic component in which either random monoallelic expression or imprinting may play a role include schizophrenia, multiple sclerosis, and diabetes.
 
Our goal is to understand the mechanism and extent of imprinting and monoallelic expression, and their possible relevance to inherited disorders, particularly those of the central nervous system. Towards this goal, we are studying a mouse locus corresponding to a human inherited mental retardation disorder known to involve imprinted genes, the Prader-Willi/Angelman Syndrome. We are also developing an assay that would make use of state-of-the-art microarray technology to probe for imprinting and monoallelic expression in the entire genome.
 

Judith Singer-Sam, Ph.D. Research

Monoallelic Expression in the Central Nervous System
Although most genes in a cell are expressed from both the maternal and paternal chromosome, there are exceptions. For example, in women, most X-linked genes are expressed from only one of the two X chromosomes, a phenomenon called X inactivation. In addition, there is a class of autosomal genes, termed imprinted genes, for which parental origin determines which allele is expressed. Finally, there are autosomal genes that appear at first glance to be bi-allelically expressed but actually show random monoallelic expression (sometimes termed allelic exclusion) at the single-cell level. These exceptions, examples of epigenetics, have proven to be of great interest for researchers because they shed light on gene regulation, chromatin structure, development, and the pattern of inheritance of certain genetic disorders.
 
My research program is focused on the potential role of allele-specific expression in development and function of the central nervous system (CNS). What is the evidence that genes likely to play a role in CNS function show such expression? Olfactory receptors, which are expressed in specialized cells of the CNS, show allelic exclusion, as does p120 catenin, which is involved in synapse formation. Intriguing recent work has shown that a number of factors involved in the immune response, including the genes for interleukin-2 and interleukin-4, also show allelic exclusion. Some of these genes are expressed in the CNS, and the possibility arises that other inflammation-sensitive genes in the CNS may show a similar pattern of expression.  Using gene expression profiling, we discovered that, Cdkn1a, coding for the cell cycle regulator p21Waf1/Cip1, is inflammation-sensitive in the CNS as well as other tissues.  While this gene is bi-allelically expressed, we expect to find additional immune response genes that do undergo monoallelic expression.
 
We have also developed an imprinting screen using expression microarrays. As a model system, we analyzed mice with imprinting defects in proximal chromosome 7; part of this region is analogous to human chromosome 15q11-q13, a locus associated with a number of behavioral and cognitive disorders including the well-studied Prader-Willi/Angelman Syndrome (PW/AS). Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the mouse PW/AS locus, in a region highly enriched in LINE-1 elements; the function of these transcripts is still unknown.  In separate work, we discovered, in collaboration with Dr. Chauncey Bowers (Department of Neurosciences) that the dense LINE-1 elements in this region are organized in a uniquely asymmetric way, perhaps related to imprinting at the locus.
 
Our current work involves the identification and characterization of genes that are subject to random monoallelic expression in the CNS. We have developed a microarray-based assay for genes that are both silenced and active at the same locus as evidenced by a dual DNA methylation pattern.  We further analyze candidate genes using SNP differences in cDNA of clonal neural stem cell lines derived from F1 hybrids of two different strains of mice. We have found a number of “hits” and are currently characterizing those that appear potentially most relevant to disorders of the CNS.
 

Singer-Sam, Judith, Ph.D. Laboratory

Laboratory of Judith Singer-Sam, Ph.D.

For a growing number of genes, only one of the two chromosomal copies (or alleles) is expressed, a phenomenon termed monoallelic expression. In some cases, there is random selection of the expressed allele; in others parental origin determines which allele is expressed, which is termed imprinting. Disorders with a genetic component in which either random monoallelic expression or imprinting may play a role include schizophrenia, multiple sclerosis, and diabetes.
 
Our goal is to understand the mechanism and extent of imprinting and monoallelic expression, and their possible relevance to inherited disorders, particularly those of the central nervous system. Towards this goal, we are studying a mouse locus corresponding to a human inherited mental retardation disorder known to involve imprinted genes, the Prader-Willi/Angelman Syndrome. We are also developing an assay that would make use of state-of-the-art microarray technology to probe for imprinting and monoallelic expression in the entire genome.
 

Research

Judith Singer-Sam, Ph.D. Research

Monoallelic Expression in the Central Nervous System
Although most genes in a cell are expressed from both the maternal and paternal chromosome, there are exceptions. For example, in women, most X-linked genes are expressed from only one of the two X chromosomes, a phenomenon called X inactivation. In addition, there is a class of autosomal genes, termed imprinted genes, for which parental origin determines which allele is expressed. Finally, there are autosomal genes that appear at first glance to be bi-allelically expressed but actually show random monoallelic expression (sometimes termed allelic exclusion) at the single-cell level. These exceptions, examples of epigenetics, have proven to be of great interest for researchers because they shed light on gene regulation, chromatin structure, development, and the pattern of inheritance of certain genetic disorders.
 
My research program is focused on the potential role of allele-specific expression in development and function of the central nervous system (CNS). What is the evidence that genes likely to play a role in CNS function show such expression? Olfactory receptors, which are expressed in specialized cells of the CNS, show allelic exclusion, as does p120 catenin, which is involved in synapse formation. Intriguing recent work has shown that a number of factors involved in the immune response, including the genes for interleukin-2 and interleukin-4, also show allelic exclusion. Some of these genes are expressed in the CNS, and the possibility arises that other inflammation-sensitive genes in the CNS may show a similar pattern of expression.  Using gene expression profiling, we discovered that, Cdkn1a, coding for the cell cycle regulator p21Waf1/Cip1, is inflammation-sensitive in the CNS as well as other tissues.  While this gene is bi-allelically expressed, we expect to find additional immune response genes that do undergo monoallelic expression.
 
We have also developed an imprinting screen using expression microarrays. As a model system, we analyzed mice with imprinting defects in proximal chromosome 7; part of this region is analogous to human chromosome 15q11-q13, a locus associated with a number of behavioral and cognitive disorders including the well-studied Prader-Willi/Angelman Syndrome (PW/AS). Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the mouse PW/AS locus, in a region highly enriched in LINE-1 elements; the function of these transcripts is still unknown.  In separate work, we discovered, in collaboration with Dr. Chauncey Bowers (Department of Neurosciences) that the dense LINE-1 elements in this region are organized in a uniquely asymmetric way, perhaps related to imprinting at the locus.
 
Our current work involves the identification and characterization of genes that are subject to random monoallelic expression in the CNS. We have developed a microarray-based assay for genes that are both silenced and active at the same locus as evidenced by a dual DNA methylation pattern.  We further analyze candidate genes using SNP differences in cDNA of clonal neural stem cell lines derived from F1 hybrids of two different strains of mice. We have found a number of “hits” and are currently characterizing those that appear potentially most relevant to disorders of the CNS.
 
Our Scientists

Our research laboratories are led by the best and brightest minds in scientific research.
 

Beckman Research Institute of City of Hope is internationally  recognized for its innovative biomedical research.
City of Hope is one of only 41 Comprehensive Cancer Centers in the country, the highest designation awarded by the National Cancer Institute to institutions that lead the way in cancer research, treatment, prevention and professional education.
Learn more about City of Hope's institutional distinctions, breakthrough innovations and collaborations.
Develop new therapies, diagnostics and preventions in the fight against cancer and other life-threatening diseases.
 
Support Our Research
By giving to City of Hope, you support breakthrough discoveries in laboratory research that translate into lifesaving treatments for patients with cancer and other serious diseases.
 
 
 
 


NEWS & UPDATES
  • As far back as he can remember, Jonathan Yamzon, M.D., wanted to be a doctor. “I knew it from the get-go,” he said, matter-of-factly. “I always envisioned it as the ideal; the supreme thing one could do with one’s life.” The youngest of six children, Yamzon was barely a toddler when his family moved to [&...
  • There’s never a “good” time for cancer to strike. With testicular cancer, the timing can seem particularly unfair. This disease targets young adults in the prime of life; otherwise healthy people unaccustomed to any serious illness, let alone cancer. And suddenly … “I can only imagine what they must...
  • Sure, a healthy lifestyle can lower a person’s risk, but the impact of specific actions is harder to tease out. Diet, exercise, tobacco use, nutritional supplements, alcohol consumption … How important are each of these factors, individually? Does strict adherence to (or rejection of) one get you a pass o...
  • Health care decisions are tough. They’re even tougher when you – or loved ones – have to make them without a plan or a conversation. National Healthcare Decisions Day, on April 16,  is a nationwide initiative to demystify the health care decision-making process and encourage families to start talking. Ult...
  • The statistics, direct from the American Cancer Society, are sobering: Cancer death rates among African-American men are 27 percent higher than for white men. The death rate for African-American women is 11 percent higher compared to white women. Hispanics have higher rates of cervical, liver and stomach cancer...
  • “Lucky” is not usually a term used to describe someone diagnosed with cancer.  But that’s how 34-year-old Alex Camargo’s doctor described him when he was diagnosed with thyroid cancer — the disease is one of the most treatable cancers at all stages. That doctor was ultimately proved righ...
  • Geoff Berman, 61, starts his day with the motto: “The sun is up. I’m vertical. It’s a good day.” Ever since he’s been in remission from lymphoma, Berman makes a special point of being grateful for each day, reminding himself that being alive is a gift. “I just enjoy living,” he said. “I give e...
  • Neural stem cells have a natural ability to seek out cancer cells in the brain. Recent research from the laboratories of Michael Barish, Ph.D., and Karen Aboody, M.D., may offer a new explanation for this attraction between stem cells and tumors. Prior to joining City of Hope, Aboody, now a professor in the Dep...
  • The American Society of Clinical Oncology, a group that includes more than 40,000 cancer specialists around the country, recently issued a list of the five most profound cancer advances over the past five decades. Near the top of the list was the introduction of chemotherapy for testicular cancer. To many in th...
  • “The dying, as a group, have been horribly underserved.” So says Bonnie Freeman, R.N., D.N.P., A.N.P.-B.C., A.C.H.P.N., a nurse practitioner in the Department of Supportive Care Medicine at City of Hope. After nearly 25 years, primarily in critical care nursing, Freeman saw that the needs of the dying were ofte...
  • “Are we the only ones who feel this way?” Courtney Bitz, L.C.S.W., a social worker in the Sheri & Les Biller Patient and Family Resource Center at City of Hope, often hears this question from couples trying to cope with a breast cancer diagnosis and still keep their relationship strong. The ques...
  • Diabetes investigators at City of Hope are studying the full trajectory of diabetes and metabolic disorders, as well as complications of the disease. One especially promising approach focuses on proteins known as growth factors. Led by Fouad Kandeel, M.D., Ph.D., chair and professor of the Department of Clinica...
  • Acute myeloid leukemia is the most common form of acute leukemia among adults, accounting for 18,000 diagnoses in 2014. Two decades ago, in 1996, the National Comprehensive Cancer Network (NCCN) published its first guidelines for treatment of acute myeloid leukemia, or AML. Margaret O’Donnell, M.D., assoc...
  • Children diagnosed with cancer are more likely than ever before to survive the disease, but with a potential new set of health problems caused by the cancer treatment itself. Those problems can particularly affect the heart, and as doctors and other health care workers try to assess how best to care for this sp...
  • Karen Reckamp, M.D., M.S., has an office next to my own, and we often see patients at the same time. As such, I’ve gotten to know her quite well over the years, and I’ve also gotten a glimpse of many of her patients. She specializes in lung cancer, and most of her patients have tumors […]